Thermostabilization of proteins

Provided are compositions comprising a cocaine esterase (CocE) and a compound that thermostabilizes the CocE. Also provided are methods of thermostabilizing a cocaine esterase. Additionally provided are methods of treating a mammal undergoing a cocaine-induced condition. Methods of determining whether a compound is a thermostabilizing agent for a protein are also provided. Uses of the above-described compositions for the treatment of a cocaine-induced condition is additionally provided. Additionally provided is an isolated nucleic acid encoding a CocE polypeptide having the substitutions L169K and G173Q, and the CocE polypeptide encoded by that nucleic acid, and pharmaceutical compositions thereof. Further provided is the use of that composition for the manufacture of a medicament for the treatment of a cocaine-induced condition and for the treatment of a cocaine-induced condition.

Labeled pkg-1-alpha-binding compounds and their use in imaging and quantifying pain

The present invention relates to the use of compounds that selectively bind to activated protein kinase G 1 alpha for imaging the anatomic basis for chronic pain. Such imaging may also be used to objectively quantify chronic pain. 1. Radiolabeled NOP46.2. The radiolabeled NOP46 of claim 1 , which is [F]-NOP46.3. The radiolabeled NOP46 of claim 1 , which is [C]-NOP46.4. A pharmaceutical composition comprising radiolabeled NOP46.5. The pharmaceutical composition of . where the radiolabeled NOP46 is [F]-NOP46.6. The pharmaceutical composition of . where the radiolabeled NOP46 is [C]-NOP46.7. A method of identifying a dorsal root ganglion associated with pain in a subject claim 4 , comprising administering claim 4 , to the subject claim 4 , a detectable amount of detectably labeled NOP compound claim 4 , and then detecting labeled NOP compound that has localized in the dorsal root ganglion.8. The method of claim 7 , where the detectably labeled NOP compound is radiolabeled NOP46.9. The method of claim 8 , where the radiolabeled NOP46 is [F]-NOP46.10. The method of claim 8 , where the radiolabeled NOP46 is [C]-NOP46.11. A method of quantifying the level of pain in a subject claim 8 , comprising administering claim 8 , to the subject claim 8 , a detectable amount of detectably labeled NOP compound claim 8 , and then quantifying the amount of labeled NOP compound that has localized in the dorsal root ganglion and/or comparing that level to a control value.12. The method of claim 11 , where the detectably labeled NOP compound is radiolabeled NOP46.13. The method of claim 12 , where the radiolabeled NOP46 is [F]-NOP46.14. The method of claim 12 , where the radiolabeled NOP46 is [C]-NOP46. This application is a continuation of International Patent Application No. PCT/US2014/044115, filed on Jun. 25, 2014, and claims priority to U.S. Provisional Application No. 61/839,649, filed Jun. 26, 2013, to both of which priority is claimed and the contents of both of which are ...

Agents for preventing and treating disorders involving modulation of the ryr receptors

The present invention provides compounds of Formula I, (I) and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells.

THERMOSTABILIZATION OF PROTEINS

Provided are compositions comprising a cocaine esterase (CocE) and a compound that thermostabilizes the CocE. Also provided are methods of thermostabilizing a cocaine esterase. Additionally provided are methods of treating a mammal undergoing a cocaine-induced condition. Methods of determining whether a compound is a thermostabilizing agent for a protein are also provided. Uses of the above-described compositions for the treatment of a cocaine-induced condition is additionally provided. Additionally provided is an isolated nucleic acid encoding a CocE polypeptide having the substitutions L169K and G173Q, and the CocE polypeptide encoded by that nucleic acid, and pharmaceutical compositions thereof. Further provided is the use of that composition for the manufacture of a medicament for the treatment of a cocaine-induced condition and for the treatment of a cocaine-induced condition. 1. A composition comprising:a cocaine esterase (CocE) polypeptide; andat least one thermostabilization compound,wherein the CocE in the presence of the compound is more thermostable than the CocE in the absence of the compound.2. The composition of claim 1 , wherein the CocE comprises:(i) an amino acid sequence of SEQ ID NO: 1;(ii) an amino acid sequence at least 90% identical to SEQ ID NO: 1 having esterase activity; or(iii) an amino acid sequence at least 90% identical to SEQ ID NO: 1 with one or more substitutions selected from the group consisting of L163V, V225I, I218L, A310D, A149S, S159A, S265A, S56G, W220A, S140A, F189L, A193D, T254R, N42V, V262L, L508G, Y152H, V160A, T172R, Y532F, T74S, W285T, L146P, D533S, A194R, G173Q, C477T, K531A, R41I, L119A, K46A, F84Y, T172R/G173Q, L169K, F189A, N197K, R182K, F189K, V190K, Q191K, A194K, and L169K/G173Q, or a combination thereof; and having esterase activity.3. The composition of claim 2 , wherein the CocE has an amino acid sequence of SEQ ID NO: 1 with one or more substitutions selected from the group consisting of: T172R claim 2 , S159A ...

N-quinolin-benzensulfonamides and related compounds for the treatment of cancer, autoimmune disorders and inflammation

The present invention relates to the NQBS class of molecules. It is based, at least in part, on the discovery that a representative group of compounds have been observed to inhibit nuclear translocation of NF-κB subunits. Without being bound by any particular theory, this inhibition of nuclear translocation may be mediated by either (i) binding of the NQBS or related compound to the C-terminus of the RHD, which specifically mediates the nuclear internalization; or (ii) NQBS-mediated stabilization of the dimer/IκB complex, disallowing dissociation of the active NF-κB monomers, and thus, inhibiting the generation of the subunits necessary to enter the nucleus. The NQBS class of molecules, and related molecules, may be used in therapeutic applications where inhibition of NF-κB translocation is beneficial, including but not limited to the treatment of cancer, autoimmune disorders, and inflammatory states.

Inhibitors of Plasmodium falciparum equilibrative nucleoside transporter type I as anti-parasitic compounds

Inhibitors of Plasmodium falciparum equilibrative nucleoside transporter type 1 are identified and methods of use as anti-parasitic compounds are provided.

Aldose reductase inhibitors and uses thereof

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Phosphodiesterase inhibitors and uses thereof

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

Neuronal pain pathway modulators

The present invention relates to compounds that may be used to inhibit activation of protein kinase G (“PKG”). It is based, at least in part, on the discovery of the tertiary structure of PKG and the identification of molecules that either bind to the active site of PKG and/or are analogs of balanol.

COMPOUNDS THAT INHIBIT NFKB AND BACE1 ACTIVITY

The present invention relates to compounds with activity as BACE1 and NFκB modulators, and methods for treating, preventing, or ameliorating neurodegenerative diseases, such as Alzheimer's disease. The present invention is also directed to the treatment of diseases related to dysfunction of cell proliferation, the immune system and/or inflammation using such compounds or pharmaceutical compositions containing such candidate compounds. 2. The composition of claim 1 , wherein R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , R claim 1 , Rand Rare independently selected for each occurrence from the group consisting of: hydrogen claim 1 , methyl claim 1 , Cl claim 1 , OCH claim 1 , CFand F.3. The composition of claim 1 , wherein Ris selected from the group consisting of phenyl claim 1 , 2-Nitrophenyl claim 1 , 3-Nitrophenyl claim 1 , 4-Nitrophenyl claim 1 , 4-Methyl-2-nitrophenyl claim 1 , 2-Methyl-5-nitrophenyl claim 1 , 2-Nitro-4-(trifluoromethyl)phenyl claim 1 , 4-Methoxy-2-nitrophenyl claim 1 , 2-Methyl-5-nitrophenyl claim 1 , 4-Methyl-2-nitrophenyl claim 1 , 4-Methylphenyl claim 1 , 2-Aminophenyl claim 1 , 2-Amino-4-methyl phenyl claim 1 , Thiophen-2-yl claim 1 , 5-Chlorothiophen-2-yl claim 1 , 5-Bromothiophen-2-yl.6. The composition of claim 5 , wherein R claim 5 , R claim 5 , R claim 5 , R claim 5 , R claim 5 , R claim 5 , R claim 5 , Rand Rare independently selected for each occurrence from the group consisting of hydrogen claim 5 , methyl claim 5 , Cl claim 5 , OCH claim 5 , CFand F.9. The composition of claim 8 , wherein R claim 8 , R claim 8 , R claim 8 , R claim 8 , R claim 8 , R claim 8 , R claim 8 , Rand Rare independently selected for each occurrence from the group consisting of hydrogen claim 8 , methyl claim 8 , Cl claim 8 , OCH claim 8 , CF claim 8 , OH claim 8 , and F.10. A method for inhibiting the activity of a β-site APP cleavage enzyme 1 (BACE1) in a cell which comprises contacting the cell with a compound of in an amount ...

PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject. 2. The compound of claim 1 , wherein A is N.3. The compound of claim 1 , wherein Ris hydrogen.4. The compound of claim 1 , wherein Ris —OCH.6. The compound of claim 5 , wherein Ris CH.8. The compound of claim 1 , wherein Ris CH—OH.9. The compound of claim 1 , wherein Ris H.10. The compound of claim 1 , wherein Ris a halogen.11. The compound of claim 1 , wherein Ris chlorine.12. The compound of claim 1 , wherein Ris —CN.13. The compound of claim 1 , wherein Ris a halogen.14. The compound of claim 1 , wherein Ris fluorine.16. The compound of claim 1 , wherein Ris hydrogen.17. The compound of claim 1 , wherein Ris C-Ccycloalkyl claim 1 , —NRR claim 1 , or —SR.18. The compound of claim 1 , wherein Ris C-Ccycloalkyl or —NRR.19. The compound of claim 1 , wherein Ris —NRR.20. The compound of claim 1 , wherein Ris —NRR claim 1 , and wherein Rand Rare each independently hydrogen claim 1 , —C-Calkyl claim 1 , —C-Ccycloalkyl claim 1 , or —C(O)R claim 1 , wherein the C-Calkyl or C-Ccycloalkyl are optionally substituted with C-Calkyl claim 1 , —C-Ccycloalkyl claim 1 , or —NRR; or claim 1 , Rand Rtogether with the nitrogen atom to which they are attached form a 3 to 8-membered heterocycle claim 1 , wherein any one of the ring carbon atoms is optionally replaced with O claim 1 , NRor N—C(O)R.21. The compound of claim 1 , wherein Ris —SR.22. The compound of claim 1 , wherein Ris —S—(C-C)-alkyl.23. The compound of claim 1 , wherein Ris C-Ccycloalkyl.24. The compound of claim 1 , wherein Ris cyclopropyl.25. The compound of claim 1 , wherein Ris dimethylamino.28. A method for screening ...

POLYAMINE INHIBITORS FOR THE TREATMENT AND PREVENTION OF PARKINSON'S DISEASE

Disclosed herein are methods for treating a disease involving α-synucleic aggregation using (1) a compound which reduces the amount of polyamines in an amount effective to reduce α-synucleic aggregation; (2) a compound which inhibits polyamine synthesis in an amount effective to reduce α-synucleic aggregation; or (3) a compound which inhibits α-synucleic aggregation in an amount effective to reduce α-synucleic aggregation. Also disclosed are methods for reducing the amount of α-synucleic aggregation in a brain cell using (1) a compound which reduces the amount of polyamines in an amount effective to reduce α-synucleic aggregation; (2) a compound which inhibits polyamine synthesis in an amount effective to reduce α-synucleic aggregation; or (3) a compound which inhibits α-synucleic aggregation in an amount effective to reduce α-synucleic aggregation. Disclosed herein are also compounds which can be used in the above described methods. 1. A method for treating a subject afflicted with a disease involving α-synucleic aggregation which comprises administering to the subject a compound which reduces the amount of polyamines and/or inhibits polyamine synthesis in the subject in an amount effective to reduce α-synucleic aggregation so as to thereby treat the subject.2. The method according to claim 1 , wherein the disease is Parkinson's Disease.3. The method according to claim 1 , wherein the compound reduces the amount of polyamines in the subject by inhibiting ornithine decarboxylase.4. The method according to claim 3 , wherein the compound is α-difluoromethylornithine (DFMO) or an analog of α-difluoromethylornithine.5. (canceled)6. The method according to claim 1 , wherein the compound reduces the amount of polyamines in the subject by inducing SSAT1 synthesis in the subject.7. The method according to claim 6 , wherein the compound is an analog of a polyamine.8. The method according to claim 7 , wherein the compound is N1 claim 7 ,N11-diethynorspermine (DENSPM).9. The ...

ANTI-DRUG VACCINES

The present invention relates to anti-drug vaccines based on conjugates between the drug and a non-immunogenic carrier protein. In preferred embodiments, it provides for anti-cocaine vaccines and their use to diminish the effects and/or use of cocaine in a subject. 1. A pharmaceutical composition comprising a drug/Self protein conjugate , in an amount effective at inducing an immune response to the drug in an immunocompetent subject , together with a suitable pharmaceutical carrier , where the Self protein is not immunogenic in said subject.2. The pharmaceutical composition of claim 1 , where the drug is cocaine.3. The pharmaceutical composition of where the drug is nicotine.4. The pharmaceutical composition of where the Self protein is human serum albumin.5. The pharmaceutical composition of where the Self protein is a human immunoglobulin.6. The pharmaceutical composition of which further comprises an adjuvant.7. A pharmaceutical composition comprising a conjugate between a Self protein and a hapten selected from the group consisting of cocaine claim 1 , a cocaine derivative claim 1 , and a transition state analog of cocaine claim 1 , in an amount effective at inducing an immune response to cocaine in an immunocompetent subject claim 1 , together with a suitable pharmaceutical carrier claim 1 , where the Self protein is not immunogenic in said subject.8. The pharmaceutical composition of where the Self protein is human serum albumin.9. The pharmaceutical composition of where the Self protein is a human immunoglobulin.10. The pharmaceutical composition of which further comprises an adjuvant.11. A method of treating a subject in need of such treatment comprising administering to the subject a pharmaceutical composition comprising a drug/Self protein conjugate claim 10 , in an amount effective at inducing an immune response to the drug in the subject claim 10 , together with a suitable pharmaceutical carrier claim 10 , where the Self protein is not immunogenic in ...

NEURONAL PAIN PATHWAY

The present invention relates to the discovery of a novel molecular pathway involved in long-term hyperexcitability of sensory neurons, which, in higher animals, is associated with persistent pain. It is based on the discovery that, following injury to an axon of a neuron, an increase in nitric oxide synthase activity results in increased nitric oxide production, which, in turn, activates guanylyl cyclase, thereby increasing levels of cGMP. Increased cGMP results in activation of protein kinase G (“PKG”), which then is retrogradely transported along the axon to the neuron cell body, where it phosphorylates MAPKerk. 2. The method of claim 1 , wherein the agent is balanol.3. The method of claim 1 , wherein the agent is a balanol variant.4. The method of claim 3 , wherein the balanol variant is selected from the group consisting of balanol-7R claim 3 , 14-decarboxy-balanol claim 3 , 10-deoxy-balanol claim 3 , balanol linked to a transport peptide claim 3 , a balanol variant linked to a transport peptide claim 3 , balanol linked to a carrier peptide claim 3 , a balanol variant linked to a carrier peptide claim 3 , balanol linked to a transport peptide and a carrier peptide claim 3 , and a balanol variant linked to a transport peptide and a carrier peptide.6. The method of claim 5 , wherein the agent is balanol.7. The method of claim 5 , wherein the agent is a balanol variant.8. The method of claim 7 , wherein the balanol variant is selected from the group consisting of balanol-7R claim 7 , 14-decarboxy-balanol claim 7 , 10-deoxy-balanol claim 7 , balanol linked to a transport peptide claim 7 , a balanol variant linked to a transport peptide claim 7 , balanol linked to a carrier peptide claim 7 , a balanol variant linked to a carrier peptide claim 7 , balanol linked to a transport peptide and a carrier peptide claim 7 , and a balanol variant linked to a transport peptide and a carrier peptide.10. The method of claim 9 , wherein the agent is balanol.11. The method of ...

HISTONE ACETYLTRANSFERASE ACTIVATORS AND USES THEREOF

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject. 8. A method for screening compounds of Formula (I) , Formula (II) , Formula (III) , or Formula (V) to treat conditions associated with accumulated amyloid-beta peptide deposits , the method comprising:a) administering a HAT Activator compound of Formula (I), Formula (II), Formula (III), or Formula (V) to an animal model of amyloid-beta peptide deposit accumulation; andb) selecting a HAT Activator compound of Formula (I), Formula (II), Formula (III), or Formula (V) that can modulate histone acetylation after administration of the HAT Activator compound in an animal model of amyloid-beta peptide deposit accumulation.9. A method for identifying a histone acetyltransferase (HAT) activator compound of Formula (I) , Formula (II) , Formula (III) , or Formula (V) to treat conditions associated with accumulated amyloid-beta peptide deposits , wherein the method comprises selecting a HAT Activator compound of Formula (I) , Formula (II) , Formula (III) , or Formula (V) having one or more of the following features:{'sub': '50', 'a) the ECof the compound is no more than about 1000 nM;'}b) the histone acetylation activity in vitro targets histone protein H2, H3, and/or H4; andc) the compound penetrates the blood brain barrier; or a combination thereof.10. The method of claim 9 , wherein the compound has a molecular mass less than about 500 Da claim 9 , has a polar surface area less than about 90 Å claim 9 , has less than 8 hydrogen bonds claim 9 , or a combination thereof claim 9 , in order to penetrate the blood brain barrier.12. The method of claim 11 , wherein the subject ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 5. The compound of claim 4 , wherein Ris hydrogen or (C-C)-alkyl;{'sup': 1', '4, 'Xand Xare N;'}{'sup': 2', '4, 'Xis CR;'}{'sup': 3', '5, 'Xis CR;'}Y is C═O;{'sup': 1', '11, 'Ais NR, O, or S;'}{'sup': '2', 'Ais N;'}{'sup': 4', '5, 'Rand Rare hydrogen;'}{'sup': 7', '10, 'sub': 1', '4', '1', '4', '1', '4', '1', '4', '1', '4, 'Rthrough Rare independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl, or (C-C)-alkylsulfonyl; and'}{'sup': '11', 'sub': 1', '4', '1', '4, 'Ris hydrogen, C-Calkyl, or C(O)O—(C-C)-alkyl.'}6. The compound of claim 5 , wherein Ris hydrogen or tert-butyl;{'sup': 1', '4, 'Xand Xare N;'}{'sup': 2', '4, 'Xis CR;'}{'sup': 3', '5, 'Xis CR;'}Y is C═O;{'sup': 1', '11, 'Ais NR, O or S;'}{'sup': '2', 'Ais N;'}{'sup': 4', '5, 'Rand Rare hydrogen;'}{'sup': 7', '10, 'Rthrough Rare independently hydrogen, halogen, or haloalkyl; and'}{'sup': '11', 'sub': 1', '4, 'Ris hydrogen, (C-C)-alkyl, or C(O)O-tert-butyl.'}8. The compound of claim 7 , wherein Ris hydrogen or (C-C)-alkyl;{'sup': 1', '4, 'Xand Xare N;'}{'sup': 2', '4, 'Xis CR;'}{'sup': 3', '5, 'Xis CR;'}Y is C═O;{'sup': 3', '11, 'Ais NR, O ...

SELECTIVE CAPTURE AND RELEASE OF ANALYTES

The described subject matter includes techniques and components for minimally invasive, selective capture and release of analytes. An aptamer is selected for its binding affinity with a particular analyte(s). The aptamer is functionalized on a solid phase, for example, microbeads, polymer monolith, microfabricated solid phase, etc. The analyte is allowed to bind to the aptamer, for example, in a microchamber. Once the analyte has been bound, a temperature control sets the temperature to an appropriate temperature at which the captured analyte is released. 1. A method for capturing and selectively releasing an analyte , comprising:(a) binding the analyte to an aptamer, the aptamer functionalized on a solid phase; and(b) setting the temperature of the aptamer such that the analyte is released from the aptamer.2. The method of claim 1 , further comprising:(c) introducing the analyte to the aptamer in an impure form;(d) washing the bound aptamer analyte complex to remove impurities; and(e) repeating (c), (a), and (d) such that the amount of bound analyte is increased.3. The method of claim 1 , further comprising:(f) collecting and detecting the analyte.4. The method of claim 1 , wherein the detecting includes performing mass spectrometry on the released analyte.5. The method of claim 1 , wherein the detecting includes detecting fluorescence intensity.6. The method of claim 1 , wherein the solid phase includes a microbead.7. The method of claim 1 , wherein the analyte includes an oligonucleotide.8. The method of claim 1 , wherein binding the analyte to the aptamer comprising binding the analyte to the aptamer at a first temperature claim 1 , and wherein setting the temperature of the aptamer comprises reducing the temperature of the aptamer to a second temperature which is lower than the first temperature.9. A method for selectively increasing the concentration of an analyte claim 1 , comprising:(a) functionalizing a solid phase with an aptamer;(b) introducing the ...

N-QUINOLIN-BENZENSULFONAMIDES AND RELATED COMPOUNDS FOR THE TREATMENT OF CANCER, AUTOIMMUNE DISORDERS AND INFLAMMATION

The present invention relates to the NQBS class of molecules. It is based, at least in part, on the discovery that a representative group of compounds have been observed to inhibit nuclear translocation of NF-κB subunits. Without being bound by any particular theory, this inhibition of nuclear translocation may be mediated by either (i) binding of the NQBS or related compound to the C-terminus of the RHD, which specifically mediates the nuclear internalization; or (ii) NQBS-mediated stabilization of the dimer/IκB complex, disallowing dissociation of the active NF-κB monomers, and thus, inhibiting the generation of the subunits necessary to enter the nucleus. The NQBS class of molecules, and related molecules, may be used in therapeutic applications where inhibition of NF-κB translocation is beneficial, including but not limited to the treatment of cancer, autoimmune disorders, and inflammatory states. 1. A method for inhibiting the activity of a Nuclear factor-κB (NFκB) in a cell which comprises contacting the cell with a compound selected from the group consisting of compounds 47 , 55 , 69 , 74 , 75 and combinations thereof , in an amount effective to inhibit Nuclear factor-κB (NFκB) activity.2. The method of claim 1 , wherein the inhibition of Nuclear factor-κB (NFκB) activity reduces nuclear translocation of the Nuclear factor-κB (NFκB).3. The method of claim 1 , wherein the cell is a mammalian cell.4. The method of claim 1 , wherein the cell is contacted in vitro.5. A method for treating a disease related to dysfunction of cell proliferation claim 1 , the immune system claim 1 , and/or inflammation in an individual claim 1 , which method comprises administering to the individual an effective amount of a compound selected from the group consisting of compounds 47 claim 1 , 55 claim 1 , 69 claim 1 , 74 claim 1 , 75 and combinations thereof.6. The method of claim 5 , where the disease is cancer.7. The method of claim 6 , where the cancer is lymphoma.8. A ...

HISTONE ACETYLTRANSFERASE ACTIVATORS AND COMPOSITIONS AND USES THEREOF

The invention provides pharmaceutical compositions and methods for treating cancer, neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein by administering a HAT modulator and a HDAC modulator to a subject. 1. A method for treating cancer in a subject in need thereof , the method comprising administering to a subject a HAT activator and a HDAC inhibitor.6. (canceled)7. (canceled)8. The method of claim 1 , wherein the cancer comprises B cell lymphoma claim 1 , colon cancer claim 1 , lung cancer claim 1 , renal cancer claim 1 , bladder cancer claim 1 , T cell lymphoma claim 1 , myeloma claim 1 , leukemia claim 1 , chronic myeloid leukemia claim 1 , acute myeloid leukemia claim 1 , chronic lymphocytic leukemia claim 1 , acute lymphocytic leukemia claim 1 , hematopoietic neoplasias claim 1 , thymoma claim 1 , lymphoma claim 1 , sarcoma claim 1 , lung cancer claim 1 , liver cancer claim 1 , non-Hodgkin's lymphoma claim 1 , Hodgkin's lymphoma claim 1 , uterine cancer claim 1 , renal cell carcinoma claim 1 , hepatoma claim 1 , adenocarcinoma claim 1 , breast cancer claim 1 , pancreatic cancer claim 1 , liver cancer claim 1 , prostate cancer claim 1 , head and neck carcinoma claim 1 , thyroid carcinoma claim 1 , soft tissue sarcoma claim 1 , ovarian cancer claim 1 , primary or metastatic melanoma claim 1 , squamous cell carcinoma claim 1 , basal cell carcinoma claim 1 , brain cancer claim 1 , angiosarcoma claim 1 , hemangiosarcoma claim 1 , bone sarcoma claim 1 , fibrosarcoma claim 1 , myxosarcoma claim 1 , liposarcoma claim 1 , chondrosarcoma claim 1 , osteogenic sarcoma claim 1 , chordoma claim 1 , angiosarcoma claim 1 , endotheliosarcoma claim 1 , lymphangiosarcoma claim 1 , lymphangioendotheliosarcoma claim 1 , synovioma claim 1 , testicular cancer claim 1 , uterine cancer claim 1 , cervical cancer claim 1 , gastrointestinal cancer claim 1 , mesothelioma claim 1 , ...

Activation or reactivation of ache

Disclosed herein is an in vitro or in vivo method of activating or reversing inactivation of acetylcholinesterase (AChE) or butyrylcholinesterase (BuchE) using compounds of the present disclosure. Also disclosed is a method of treating a subject exposed to a nerve agent using such compounds. Also disclosed is a method of treating organophosphate poisoning in a subject using such compounds. Also disclosed is a method of modulating neuronal signaling and transmission in a subject using such compounds.

TRIAZOLOPYRIMIDINES, THEIR PREPARATION AND USE

The present invention provides a compound having the structure: 4. The compound of claim 1 ,{'sub': 1', '2', '3', '4', '5, 'wherein one of R, R, R, R, and Ris other than H, or'}{'sub': 1', '2', '3', '4', '5, 'wherein two of R, R, R, R, and Rare other than H.'}5. (canceled)7. The compound of claim 6 , wherein{'sub': 7', '8', '9', '3', '2', '3', '3', '3', '3', '3', '2, 'R, Rand Rare each, independently, H, Cl, Br, F, OCH, OCHCH, CF, CN, CH, CHCH, C(O)OH or C(O)—NH, or'}{'sub': 7', '8', '9', '2', '2', '2', '2', '3', '2', '2', '2', '2', '2', '2', '2', '2, 'R, Rand Rare each, independently, H, CHCHOH, CHCHOCH, CHCHOAc, CHCHCl, CHCHF or CHCHBr, or'}{'sub': 7', '8', '9, 'R, Rand Rare each, independently, H, halogen or alkyl, or'}{'sub': 7', '8', '9', '7', '8', '9', '3', '8', '9', '7', '8', '9, 'two of R, Rand Rare each H and the remaining one of R, Rand Ris other than H; or wherein one of R, Rand Ris H and the remaining two of R, Rand Rare each other than H.'}810-. (canceled)1315-. (canceled)1723-. (canceled)2526-. (canceled)32. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.33. A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of a compound of .34. (canceled)35. The method of claim 33 , wherein the amount of the compound is effective to lower the serum concentration of RBP4 in the mammal or to lower the retinal concentration of a bisretinoid in lipofuscin in the mammal without substantially activating PPAR gamma in the mammal.36. (canceled)37. The method of claim 35 , wherein the bisretinoid is A2E claim 35 , isoA2E claim 35 , A2-DHP-PE or atRAL di-PE.38. The method of claim 33 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration claim 33 , dry (atrophic) Age-Related Macular Degeneration claim 33 , Stargardt Disease ...

POTENT NON-UREA INHIBITORS OF SOLUBLE EPOXIDE HYDROLASE

The present invention relates to compounds that exhibit vasodilatory and anti-inflammatory effects by inhibiting the activity of soluble epoxide hydrolase (sEH). The present invention is also directed to methods of identifying such compounds, and use of such compounds for the treatment of diseases related to dysfunction of vasodilation, inflammation, and/or endothelial cells. In particular non-limiting embodiments, components of the invention may be used to treat hypertension. 2. The compound of claim 1 , wherein Ris selected from the group consisting of a substituted aryl having one or more substituent which is a halogen.3. The compound of claim 2 , wherein the halogen is selected from the group consisting of fluorine or chlorine.4. The compound of claim 1 , wherein Ris —S(O)R claim 1 , and wherein Ris selected from the group consisting of a substituted aryl having one or more substituent and an unsubstituted aryl.5. The compound of claim 4 , wherein Ris a substituted aryl and the one or more substituent is selected from the group consisting of a hydrophobic alkyl group and a halide.6. The compound of claim 4 , wherein Ris a substituted aryl having one or more substituent claim 4 , and wherein at least one of the one or more substituents is in the ortho position.7. The compound of claim 6 , wherein the one or more substituents in the ortho position is selected from the group consisting of a bromide claim 6 , fluoride and methyl.12. The compound of claim 1 , wherein the compound is formulated as a pharmaceutical formulation. This application is a divisional of U.S. patent application Ser. No. 14/182,175, filed Feb. 17, 2014, which is a continuation of U.S. application Ser. No. 13/178,117, filed Jul. 7, 2011, now U.S. Pat. No. 8,653,273, which is a continuation of International Application No. PCT/US2009/057553, filed Sep. 18, 2009, which claims the benefit of U.S. Provisional Application No. 61/143,397, filed Jan. 8, 2009, priority to each of which is claimed, and ...

Aldose reductase inhibitors and uses thereof

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Targeting Casein Kinase-1 and PI3K/AKT/mTOR Pathways for Treatment of c-Myc-Overexpressing Cancers, Organ Transplant Associated Complications and Autoimmune Diseases

The invention relates to the co-administration of select proteasome and PI3K inhibitors is useful for treating c-Myc-overexpressing cancers, particularly hematological cancers such as aggressive B- and T-cell lymphomas. In exemplified embodiments, coadministration of a dual PI3K/CK-1 inhibitor with a proteasome inhibitor synergistically increases cell death of aggressive B- and T-cell lymphomas as well as multiple myeloma over the individual or additive effect of either or both agents. This synergistic effect is associated with the previously unknown inhibition of the kinase casein kinase 1 epsilon (CK-1ε) by a PI3K inhibitor, such as TGR-1202. Accordingly, use of PI3K inhibitors that possess CK-1ε inhibition in combination with proteasome inhibitors provides a new therapy regime for treating c-Myc-overexpressing cancers, and particularly hematological cancers. 1. A method for treating a c-Myc-overexpressing cancer in a subject comprising co-administering a therapeutically effective amount of a dual PI3K/CK-1 inhibitor with a therapeutically effective amount of a proteasome inhibitor , or optionally , co-administering a therapeutically effective amount of a PI3K inhibitor , a CK-1 inhibitor and a proteasome inhibitor.2. The method of claim 1 , wherein the cancer is a hematological cancer.3. The method of claim 1 , wherein the cancer is a B cell cancer.4. The method of claim 1 , wherein the B cell cancer is multiple myeloma or lymphoma.5. The method of claim 1 , wherein the cancer is cancer solid tumor in an organ selected from the group consisting of the lung claim 1 , breast claim 1 , prostate claim 1 , ovary claim 1 , colon claim 1 , kidney claim 1 , and liver.6. The method of claim 1 , wherein the PI3K inhibitor comprises TGR-1202 claim 1 , or an therapeutically active analog or derivative thereof claim 1 , or pharmaceutically acceptable salt of any of the foregoing.7. The method of claim 1 , wherein the proteasome inhibitor comprises carfilzomib claim 1 , or an ...

PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject. 143-. (canceled)45. The method of claim 44 , wherein the effective amount is at least about 1 mg/kg body weight claim 44 , at least about 2 mg/kg body weight claim 44 , at least about 3 mg/kg body weight claim 44 , at least about 4 mg/kg body weight claim 44 , at least about 5 mg/kg body weight claim 44 , at least about 6 mg/kg body weight claim 44 , at least about 7 mg/kg body weight claim 44 , at least about 8 mg/kg body weight claim 44 , at least about 9 mg/kg body weight claim 44 , or at least about 10 mg/kg body weight.46. The method of claim 44 , wherein A is N.47. The method of claim 44 , wherein Ris hydrogen.48. The method of claim 44 , wherein Ris —OCH.50. The method of claim 48 , wherein Ris CH.52. The method of claim 44 , wherein Ris CH—OH.53. The method of claim 44 , wherein Ris H.54. The method of claim 44 , wherein Ris a halogen.55. The method of claim 44 , wherein Ris chlorine.56. The method of claim 44 , wherein Ris —CN.57. The method of claim 44 , wherein Ris a halogen.58. The method of claim 44 , wherein Ris fluorine.60. The method of claim 44 , wherein Ris hydrogen.61. The method of claim 44 , wherein Ris C-Ccycloalkyl claim 44 , —NRR claim 44 , or —SR.62. The method of claim 44 , wherein Ris C-Ccycloalkyl or —NRR.63. The method of claim 44 , wherein Ris —NRR.64. The method of claim 44 , wherein Ris —NRR claim 44 , and wherein Rand Rare each independently hydrogen claim 44 , —C-Calkyl claim 44 , —C-Ccycloalkyl claim 44 , or —C(O)R claim 44 , wherein the C-Calkyl or C-Ccycloalkyl are optionally substituted with —C-Calkyl claim 44 , —C-Ccycloalkyl claim 44 , ...

AGENTS FOR PREVENTING AND TREATING DISORDERS INVOLVING MODULATION OF THE RYANODINE RECEPTORS

Methods for reducing toxicity or side effects caused by administration of a rycal compound for repairing ryanodine receptor channel leaks when treating a disorder in a subject caused by such leaks. These methods are based upon the selection for administration of those rycal compounds having properties including an ECvalue of 102 nM when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated RyR2 or less and less than 50% inhibition of the hERG K channel (I) when administered at 10 μM to reduce compound toxicity or side effects after administration compared to other rycal compounds not having those properties. 1. in a method of treating a disorder in a subject caused by a ryanodine receptor channel leak by administering to the subject a therapeutically effective amount of a rycal compound to repair the channel leak to treat the disorder , the improvement which comprises selecting for administration a rycal compound having properties including an ECvalue of 102 nM or less when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated RyR2 and less than 50% inhibition of the hERG K channel (I) when administered at 10 μM to reduce compound toxicity or side effects after administration compared to other rycal compounds not having those properties.2. The method of claim 1 , wherein the disorder is selected from the group consisting of cardiac disorders or diseases claim 1 , skeletal muscular disorders or diseases claim 1 , cognitive disorders or diseases claim 1 , malignant hyperthermia claim 1 , diabetes claim 1 , and sudden infant death syndrome.3. The method of claim 2 , wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders or diseases; exercise-induced irregular heartbeat disorders or diseases; heart failure claim 2 , congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; the skeletal muscular disorders or diseases ...

Histone acetyltransferase activators and uses thereof

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tan protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

INHIBITORS OF PLASMODIUM FALCIPARUM EQUILIBRATIVE NUCLEOSIDE TRANSPORTER TYPE I AS ANTI-PARASITIC COMPOUNDS

Inhibitors of equilibrative nucleoside transporter type 1 are identified and methods of use as anti-parasitic compounds are provided. 131-. (canceled)32. A compound N ,N′-1 ,3-benzothiazole-2 ,6-diyldi(2-furamide);2-[2-(2-methylphenyl)vinyl]-4(3H)-quinazolinone;2-(1-methyl-1H-indol-3-yl)-2-oxo-N-[4-(pyrrolidin-1-ylcarbonyl)phenyl]acetamide;N-{4-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]phenyl}-2-furamide;2-bromo-N-(4-[1,3]oxazolo[4,5-b]pyridin-2-ylphenyl)benzamide;3-fluoro-N-(3-[1,3]oxazolo[4,5-b]pyridin-2-ylphenyl)benzamide;2-methoxy-N-(3-[1,3]oxazolo[4,5-b]pyridin-2-ylphenyl)benzamide; orN-(4-chloro-3-[1,3]oxazolo[4,5-b]pyridin-2-ylphenyl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof.33. A pharmaceutical composition comprising a) pharmaceutically effective amount of the compound of claim 32 , or a pharmaceutically acceptable salt claim 32 , solvate claim 32 , poly-morph claim 32 , tautomer or prodrug thereof claim 32 , and b) a pharmaceutically acceptable carrier claim 32 , diluent claim 32 , excipient and/or adjuvant.34PlasmodiumPlasmodiumPlasmodium. A method for inhibiting an Equilibrative Nucleoside Transporter (ENT) of a species comprising contacting the species with the compound of claim 32 , in an amount effective to inhibit the ENT of the species.35. The method of claim 34 , wherein the ENT is an ENT1 claim 34 , ENT2 claim 34 , ENT3 claim 34 , or ENT4.36. The method of claim 35 , wherein the ENT is an ENT1.37plasmodiumP. falciparum, P. berghei, P. vivax, P. ovale, P. malariaeP. knowlesi.. The method of claim 34 , wherein species is or38plasmodiumPlasmodium falciparum.. The method of claim 37 , wherein the species is39. A method of treatment or prophylaxis of a disorder or disease mediated by infection with a parasitic purine auxotroph claim 32 , comprising administering to a patient in need thereof a therapeutically effective amount of the compound of .40. The method of claim 39 , wherein the disorder or disease is malaria.41. The method of ...

NEURONAL PAIN PATHWAY MODULATORS

The present invention relates to compounds that may be used to inhibit activation of protein kinase G (“PKG”). It is based, at least in part, on the discovery of the tertiary structure of PKG and the identification of molecules that either bind to the active site of PKG and/or are analogs of balanol. This application is a continuation application of Ser. No. 11/674,965, filed Feb. 14, 2007 and claims priority to U.S. Provisional Application Ser. No. 60/773,691, filed Feb. 14, 2006, and U.S. Provisional Application Ser. No. 60/815,980, filed Jun. 23, 2006. The contents of these three referenced applications are incorporated herein by reference in their entireties.The subject matter of this application was developed at least in part under National Institutes of Health Grants NS12250 and NS35979, so that the United States Government has certain rights herein.The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy is named 0700505389_SL.txt and is 51,104 bytes in size.The present invention relates to compounds that inhibit the activated form of protein kinase G (“PKG”) and their use in the alleviation of pain, particularly in the context of chronic pain syndromes.Pain is perceived as a result of communication between the two main divisions —central and peripheral—of the nervous system. While the two divisions work together to produce our subjective experience, the central and peripheral nervous systems are anatomically and functionally different.A painful stimulus impinging on a specialized pain receptor is propagated along a peripheral branch of a primary nociceptive sensory neuron whose cell body resides within a dorsal root ganglion (part of the peripheral nervous system) and then along a central branch of the neuron that enters the spinal cord (central nervous system). The signal is subsequently relayed to a second order neuron in the spinal ...

HISTONE ACETYLTRANSFERASE MODULATORS AND USES THEREOF

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject. 24. The method of claim 23 , wherein the subject exhibits abnormally elevated levels of amyloid beta plaques.25. The method of or wherein the subject is afflicted with Alzheimer's disease claim 23 , Lewy body dementia claim 23 , inclusion body myositis claim 23 , or cerebral amyloid angiopathy.26. The method of any of - claim 23 , wherein the Aβ protein deposit comprises an Aβisomer claim 23 , an Aβisomer claim 23 , or a combination thereof.27. A method for treating Alzheimer's Disease in a subject claim 23 , the method comprising administering to a subject a therapeutic amount of a compound of any of - or a pharmaceutical composition comprising a compound of any of -.28. A method for increasing memory retention in a subject afflicted with a neurodegenerative disease claim 23 , the method comprising administering to a subject a therapeutic amount of a compound of any of - or a pharmaceutical composition comprising a compound of any of -.29. A method for increasing synaptic plasticity in a subject afflicted with a neurodegenerative disease claim 23 , the method comprising administering to a subject a therapeutic amount of a compound of any of - or a composition comprising a compound of any of - that increases histone acetylation in the subject.30. A method for treating a neurodegenerative disease in a subject claim 23 , the method comprising administering to a subject a therapeutic amount of a compound of any of - or a pharmaceutical composition comprising a compound of any of - claim 23 , thereby treating the neurodegenerative disease in the subject.31. A method for ...

HISTONE ACETYLTRANSFERASE ACTIVATORS AND USES THEREOF

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject. 2. The method of claim 1 , wherein the subject exhibits abnormally elevated levels of amyloid beta plaques.3. The method of claim 1 , wherein the subject is afflicted with Alzheimer's disease claim 1 , Lewy body dementia claim 1 , inclusion body myositis claim 1 , or cerebral amyloid angiopathy.4. The method of claim 1 , wherein the Aβ protein deposit comprises an Aβ40 isomer claim 1 , an Aβ42 isomer claim 1 , or a combination thereof.6. A method for treating Alzheimer's Disease claim 1 , the method comprising administering to a subject a therapeutic amount of a pharmaceutical composition comprising a HAT activator compound.13. A method for ameliorating symptoms of Parkinson's Disease claim 1 , the method comprising administering to a subject a therapeutic amount of a pharmaceutical composition comprising a HAT activator compound.15. A method for treating Huntington's Disease claim 1 , the method comprising administering to a subject a therapeutic amount of a pharmaceutical composition comprising a HAT activator compound.16. The method of claim 1 , wherein the effective amount is at least about 1 mg/kg body weight claim 1 , at least about 2 mg/kg body weight claim 1 , at least about 3 mg/kg body weight claim 1 , at least about 4 mg/kg body weight claim 1 , at least about 5 mg/kg body weight claim 1 , at least about 6 mg/kg body weight claim 1 , at least about 7 mg/kg body weight claim 1 , at least about 8 mg/kg body weight claim 1 , at least about 9 mg/kg body weight claim 1 , at least about 10 mg/kg body weight claim 1 , at least about 15 mg/kg body weight claim 1 ...

NOVEL PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibition of phosphodiesterase comprising contacting phosphodiesterase with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. The invention further provides for methods for treatment of neurodegenerative diseases, increasing memory or long term potentiation with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the phosphodiesterase is PDE5. 5. The compound of claim 1 , wherein X is —(C-C)-alkyl.6. The compound of claim 1 , wherein X is —(C-C)-alkyl substituted with at least one D.7. The compound of claim 1 , wherein{'sup': '4', 'A is NR;'}V is a bond or C(O);{'sup': '13', 'W is a bond or NR;'}{'sub': 1', '3', '1', '3, 'X is —(C-C)-alkyl or —(C-C)-alkyl substituted with at least one D;'}{'sup': '5', 'Y is NR;'}{'sup': '1', 'sub': 1', '3, 'Ris halogen or —(C-C)-haloalkyl;'}{'sup': 2', '6, 'Ris —OR;'}{'sup': '3', 'sub': '3', 'Ris hydrogen, —OMe, —CF, —CN or halogen;'}{'sup': 5', '7, 'sub': 1', '3', '1', '3, 'Ris hydrogen, —(C-C)-alkyl, —(C-C)-cycloalkyl, or —C(O)R;'}{'sup': '6', 'sub': 1', '3', '1', '3, 'Ris —(C-C)-alkyl or —(C-C)-haloalkyl;'}{'sup': '7', 'sub': 1', '3, 'Ris —(C-C)-alkyl;'}{'sup': '8', 'sub': 1', '3, 'Ris hydrogen or —(C-C)-alkyl;'}{'sup': '13', 'sub': 1', '3, 'Ris hydrogen or —(C-C)-alkyl; and'}m and n are independently 0, 1 or 2, provided that the sum of m+n is an integer from 2-3.8. The compound of claim 1 , whereinA is NH;V is a bond or C(O);{'sup': '13', 'W is a bond or NR;'}{'sub': 1', '3', '1', '3, 'X is —(C-C)-alkyl or —(C-C)-alkyl substituted with at least one D;'}{'sup': '5', 'Y is NR;'}{'sup': '1', 'Ris halogen;'}{'sup': 2', '6, 'Ris —OR;'}{'sup': '3', 'sub': '3', 'Ris ...

SELECTIVE CAPTURE AND RELEASE OF ANALYTES

The described subject matter includes techniques and components for minimally invasive, selective capture and release of analytes. An aptamer is selected for its binding affinity with a particular analyte(s). The aptamer is functionalized on a solid phase, for example, microbeads, polymer monolith, microfabricated solid phase, etc. The analyte is allowed to bind to the aptamer, for example, in a microchamber. Once the analyte has been bound, a temperature control sets the temperature to an appropriate temperature at which the captured analyte is released. 1. A method for capturing and selectively releasing an analyte , comprising:(a) binding the analyte to an aptamer, the aptamer functionalized on a solid phase; and(b) setting the temperature of the aptamer such that the analyte is released from the aptamer.2. The method of claim 1 , further comprising:(c) introducing the analyte to the aptamer in an impure form;(d) washing the bound aptamer analyte complex to remove impurities; and(e) repeating (c), (a), and (d) such that the amount of bound analyte is increased.3. The method of claim 1 , further comprising:(f) collecting and detecting the analyte.4. The method of claim 1 , wherein the detecting includes performing mass spectrometry on the released analyte.5. The method of claim 1 , wherein the detecting includes detecting fluorescence intensity.6. The method of claim 1 , wherein the solid phase includes a microbead.7. The method of claim 1 , wherein the analyte includes an oligonucleotide.8. The method of claim 1 , wherein binding the analyte to the aptamer comprising binding the analyte to the aptamer at a first temperature claim 1 , and wherein setting the temperature of the aptamer comprises reducing the temperature of the aptamer to a second temperature which is lower than the first temperature.9. A method for selectively increasing the concentration of an analyte claim 1 , comprising:(a) functionalizing a solid phase with an aptamer;(b) introducing the ...

Compounds, Compositions, and Methods for Treating T-Cell Acute Lymphoblastic Leukemia

In an aspect, the disclosure provides for compounds (II), compositions, and methods of administering the compounds and compositions to a patient in need thereof. In another aspect, the disclosure relates to compounds and compositions for treating cancer, for example, lymphoid leukemia. The disclosure further provides for compounds which inhibit two phosphoinositide 3-kinase (PI3K) isoforms, y and δ, pharmaceutical compositions comprising said compounds, and methods of using said compounds and pharmaceutical compositions for treatment, amelioration, and/or prevention of non-Hodgkin lymphoma. 3. A compound according to claim 2 , wherein:{'sup': 1', '2', '3', '4', '5, 'R, R, R, R, and Rare independently hydrogen, methyl, F or deuterium;'}{'sup': '9', 'Ris Cl, F or methyl; and'}{'sup': 10', '11', '12, 'R, R, and Rare each hydrogen.'}5. A compound according to claim 1 , wherein:{'sup': 1', '2', '3', '4', '5, 'R, R, R, R, and Rare independently hydrogen, F, or deuterium;'}{'sup': '6', 'Ris methyl; and'}{'sup': '9', 'Ris Cl or methyl.'}79.-. (canceled)12. A compound according to claim 1 , wherein the compound is a (S) or (R) stereoisomer with respect to the chiral carbon to which Ris attached claim 1 , or the compound is a non-racemic mixture of the (S) and (R) stereoisomers claim 1 , or the compound is the (S) isomer alone or the (R) isomer alone.13. A compound according to claim 1 , wherein the compound is an inhibitor of PI3Kδ claim 1 , an inhibitor of PI3Kγ claim 1 , or an inhibitor of both PI3Kδ and PI3Kγ.14. A compound according to claim 13 , wherein the compound is an inhibitor of both PI3Kδ and PI3Kγ.15. A pharmaceutical composition comprising a compound of and a pharmaceutically acceptable carrier.16. A compound according to claim 1 , wherein the compound is in the form of a pharmaceutical composition claim 1 , wherein the compound is a dual inhibitor of PI3Kδ and PI3Kγ claim 1 , or wherein the composition comprises one active agent that is a PI3Kδ inhibitor and a ...

HISTONE ACETYLTRANSFERASE ACTIVATORS AND USES THEREOF

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject. 4. The compound of claim 3 , wherein{'sup': '1', 'sub': 1', '6, 'Ris OH, or C-C-alkyl; and'}{'sup': 2', '5', '+', '−, 'sub': 2', '6', '3', '1', '6, 'Ris OH, —O—(C-C-alkyl)-N(R)halogen, or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '2', '6', '3, 'wherein when Ris OH, Ris OH, —O—(C-C-alkyl)-phenyl, or —O—(C-C-alkyl)-N(R)halogen; and'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '1', '6', '2', '6', '3, 'when Ris C-C-alkyl, Ris OH, —O—(C-C-alkyl)-phenyl, or —O—(C-C-alkyl)-N(R)halogen.'}5. The compound of claim 4 , wherein{'sup': '1', 'sub': 1', '2, 'Ris OH, or C-C-alkyl; and'}{'sup': '2', 'sub': 1', '3, 'Ris OH, or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2, 'sub': 1', '3, 'wherein when Ris OH, Ris OH or —O—(C-C-alkyl)-phenyl; and'}{'sup': 1', '2, 'sub': 1', '2', '1', '3, 'when Ris C-C-alkyl, Ris —O—(C-C-alkyl)-phenyl.'}15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.16. A method for reducing amyloid beta (Aβ) protein deposits in a subject claim 1 , the method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'administering to the subject an effective amount of a composition comprising a compound of , or a pharmaceutically acceptable salt or solvate thereof'}thereby decreasing Aβ protein deposits in the subject.17. The method of claim 16 , wherein the subject exhibits abnormally elevated levels of amyloid beta plaques.18. The method of wherein the subject is afflicted with Alzheimer's disease claim 17 , Lewy body ...

COMPOUNDS THAT INHIBIT NFkB AND BACE1 ACTIVITY

The present invention relates to compounds with activity as BACE1 and NFκB modulators, and methods for treating, preventing, or ameliorating neurodegenerative diseases, such as Alzheimer's disease. The present invention is also directed to the treatment of diseases related to dysfunction of cell proliferation, the immune system and/or inflammation using such compounds or pharmaceutical compositions containing such candidate compounds. 2. The composition of claim 1 , wherein R claim 1 , R claim 1 , R claim 1 , R claim 1 , and Rare independently selected for each occurrence from the group consisting of:{'sub': 3', '3, 'hydrogen, methyl, Cl, OCH, CFand F.'}3. The composition of claim 1 , wherein Ris selected from the group consisting of phenyl claim 1 , 2-Nitrophenyl claim 1 , 3-Nitrophenyl claim 1 , 4-Nitrophenyl claim 1 , 4-Methyl-2-nitrophenyl claim 1 , 2-Methyl-5-nitrophenyl claim 1 , 2-Nitro-4-(trifluoromethyl)phenyl claim 1 , 4-Methoxy-2-nitrophenyl claim 1 , 2-Methyl-5-nitrophenyl claim 1 , 4-Methyl-2-nitrophenyl claim 1 , 4-Methylphenyl claim 1 , 2-Aminophenyl claim 1 , 2-Amino-4-methyl phenyl claim 1 , Thiophen-2-yl claim 1 , 5-Chlorothiophen-2-yl claim 1 , 5-Bromothiophen-2-yl.49-. (canceled)10. A method for inhibiting the activity of a β-site APP cleavage enzyme 1 (BACE1) in a cell which comprises contacting the cell with a compound of in an amount effective to inhibit β-site APP cleavage enzyme 1 activity.11. The method of claim 10 , wherein the inhibition of β-site APP cleavage enzyme 1 activity reduces the metabolism of an amyloid precursor protein (APP).12. The method of claim 10 , wherein the cell is a mammalian cell.13. The method of claim 10 , wherein the cell is contacted in vitro.14. A method for treating Alzheimer's disease in an individual claim 1 , which method comprises administering to the individual an effective amount of a compound according to .15. A method for inhibiting the activity of a Nuclear factor-κ B (NFκB) in a cell which comprises ...

Compounds For Reducing c-Myc In c-Myc Overexpressing Cancers Background

The invention relates to new compounds that reduce c-Myc expression and useful for cancer treatment, particularly hematological cancers such as aggressive B- and T-cell lymphomas. The new compounds may be combined with adjunct c-Myc inhibor agents such as a PI3K inhibitor, CK-1 inhibitor, Akt-inhibitor, proteasome inhibitor and/or mTor inhibitor. The c-Myc reducing agent may be provided as a lead-in treatment to reduce or initiate reduction of c-Myc prior to adminstration of the adjunct cancer therapeutic agent. Treatment with a c-Myc reducing agent modulates the disease state of the c-Myc overexpressing cancer making it less malignant and more susceptible to adjunctive cancer therapies. 2. The compound of wherein the following compounds are further excluded:{'sub': 1', '3', '7, 'compounds of formula I wherein at the same time R is group A, Ris CH, Ris N and Ris J;'}{'sub': 1', '2', '3', '7, 'img': {'@id': 'CUSTOM-CHARACTER-00020', '@he': '3.56mm', '@wi': '7.79mm', '@file': 'US20190194212A1-20190627-P00001.TIF', '@alt': 'custom-character', '@img-content': 'character', '@img-format': 'tif'}, 'compounds of formula II wherein at the same time R is group A, Ris CH, Ris O, Ris C, represents a double bond, and Ris J.'}3. The compound of wherein Ris substituted Calkyl or unsubstituted Calkyl.4. The compound of wherein Ris substituted or unsubstituted propyl claim 3 , substituted or unsubstituted butyl claim 3 , or substituted or unsubstituted ethyl.5. The compound of claim 1 , wherein Ris N.6. The compound of claim 1 , wherein n for Ris 1 or 2 and at least one Ris halogen.7. The compound of wherein halogen is F.8. The compound of wherein n for Ris 1 claim 7 , and Ris located at position 5 of the quinazolin-4-one ring to which it is attached.9. The compound of claim 1 , wherein n for Ris 0.10. The compound of claim 1 , wherein R is group A.11. The compound of any claim 1 , wherein Ris J claim 1 , or is not J.12. (canceled)13. The compound of any of claim 1 , wherein n for ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The method of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The method of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.7. The method of claim 1 , wherein the cardiovascular disorder is atherosclerosis claim 1 , coronary artery disease claim 1 , peripheral vascular disease or stroke.8. The method of claim 4 , wherein the cardiovascular disorder is atherosclerosis claim 4 , coronary artery disease claim 4 , peripheral vascular disease or stroke.9. The method of claim 5 , wherein the cardiovascular disorder is atherosclerosis claim 5 , coronary artery disease claim 5 , peripheral vascular disease or stroke.10. The method of claim 6 , wherein the cardiovascular disorder is atherosclerosis claim 6 , coronary artery disease claim 6 , peripheral vascular disease or stroke.11. The method of claim 1 , wherein the subject is a human.12. The method of claim 4 , wherein the ...

PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject. 2. The method of claim 1 , wherein the effective amount is at least about 1 mg/kg body weight claim 1 , at least about 2 mg/kg body weight claim 1 , at least about 3 mg/kg body weight claim 1 , at least about 4 mg/kg body weight claim 1 , at least about 5 mg/kg body weight claim 1 , at least about 6 mg/kg body weight claim 1 , at least about 7 mg/kg body weight claim 1 , at least about 8 mg/kg body weight claim 1 , at least about 9 mg/kg body weight claim 1 , or at least about 10 mg/kg body weight.3. The method of claim 1 , wherein A is N.4. The method of claim 1 , wherein Ris hydrogen.5. The method of claim 1 , wherein Ris —OCH.7. The method of claim 6 , wherein Ris CH.9. The method of claim 1 , wherein Ris CH—OH.10. The method of claim 1 , wherein Ris H.11. The method of claim 1 , wherein Ris a halogen.12. The method of claim 1 , wherein Ris chlorine.13. The method of claim 1 , wherein Ris —CN.14. The method of claim 1 , wherein Ris a halogen.15. The method of claim 1 , wherein Ris fluorine.17. The method of claim 1 , wherein Ris hydrogen.18. The method of claim 1 , wherein Ris C-Ccycloalkyl claim 1 , —NRR claim 1 , or —SR.19. The method of claim 1 , wherein Ris C-Ccycloalkyl or —NRR.20. The method of claim 1 , wherein Ris —NRR.21. The method of claim 1 , wherein Ris —NRR claim 1 , and wherein Rand Rare each independently hydrogen claim 1 , —C-Calkyl claim 1 , —C-Ccycloalkyl claim 1 , or —C(O)R claim 1 , wherein the C-Calkyl or C-Ccycloalkyl are optionally substituted with —C-Calkyl claim 1 , —C-Ccycloalkyl claim 1 , or —NRR; or claim 1 , Rand Rtogether with the nitrogen ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The method of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The method of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.7. The method of claim 1 , wherein the cardiovascular disorder is atherosclerosis claim 1 , coronary artery disease claim 1 , peripheral vascular disease or stroke.8. The method of claim 4 , wherein the cardiovascular disorder is atherosclerosis claim 4 , coronary artery disease claim 4 , peripheral vascular disease or stroke.9. The method of claim 5 , wherein the cardiovascular disorder is atherosclerosis claim 5 , coronary artery disease claim 5 , peripheral vascular disease or stroke.10. The method of claim 6 , wherein the cardiovascular disorder is atherosclerosis claim 6 , coronary artery disease claim 6 , peripheral vascular disease or stroke.11. The method of claim 1 , wherein the subject is a human.12. The method of claim 4 , wherein the ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The method of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The method of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.7. The method of claim 1 , wherein the complication of diabetes is diabetic nephropathy claim 1 , diabetic neuropathy or diabetic retinopathy.8. The method of claim 4 , wherein the complication of diabetes is diabetic nephropathy claim 4 , diabetic neuropathy or diabetic retinopathy.9. The method of claim 5 , wherein the complication of diabetes is diabetic nephropathy claim 5 , diabetic neuropathy or diabetic retinopathy.10. The method of claim 6 , wherein the complication of diabetes is diabetic nephropathy claim 6 , diabetic neuropathy or diabetic retinopathy.11. The method of claim 1 , wherein the subject is a human.12. The method of claim 4 , wherein the subject is a human.13. The method of claim 5 , wherein the subject is a human.14. The ...

INHIBITORS OF CENTRAL NERVOUS SYSTEM VASOACTIVE INHIBITORY PEPTIDE RECEPTOR 2

The present invention relates to compounds that inhibit VIPRin the CNS, pharmaceutical compositions comprising said compounds, and methods of using such compounds and compositions in the treatment of a CNS disorder such as a behavioral disorder, including but not limited to schizophrenia. 14. The method of claim 13 , wherein the central nervous system disorder is selected from the group consisting of a psychiatric disorder claim 13 , a neurodevelopmental disorder claim 13 , and a behavioral disorder.15. The method of claim 14 , wherein the central nervous system disorder is a psychiatric disorder.16. The method of claim 15 , wherein the psychiatric disorder is schizophrenia.17. The method of claim 15 , wherein the psychiatric disorder is bipolar disorder.18. The method of claim 15 , wherein the psychiatric disorder is borderline personality disorder.19. The method of claim 15 , wherein the psychiatric disorder is schizoid disorder.20. The method of claim 15 , wherein the psychiatric disorder is major depression.21. The method of claim 15 , wherein the psychiatric disorder is obsessive compulsive disorder.23. The method of claim 22 , wherein the neurodevelopmental disorder is an autism spectrum disorder.24. The method of claim 23 , wherein the autism spectrum disorder is selected from the group consisting of autism claim 23 , Asperger's syndrome claim 23 , childhood disintegrative disorder claim 23 , Rett syndrome claim 23 , and pervasive developmental disorder not otherwise specified.26. The method of claim 25 , wherein the behavioral disorder is a sleep disorder.27. The method of claim 26 , wherein the sleep disorder is selected from the group consisting of insomnia claim 26 , narcolepsy claim 26 , and sleep deprivation.30. The method of claim 29 , wherein the compound is contacted to the cell in an amount effective to reduce or inhibit the ability of VIPR2 protein to activate cyclic-AMP signaling.31. The method of claim 29 , wherein the compound is contacted to ...

NOVEL PHOSPHODIESTERASE INHIBITORS AND USES THEREOF

The invention provides for novel benzonaphthyridine derivatives and compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the compounds are phosphodiesterase inhibitors. The invention further provides for methods for inhibition of phosphodiesterase comprising contacting phosphodiesterase with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. The invention further provides for methods for treatment of neurodegenerative diseases, increasing memory or long term potentiation with novel benzonaphthyridine derivatives or compositions comprising novel benzonaphthyridine derivatives. In some embodiments, the phosphodiesterase is PDE5. 2. The compound of claim 1 , wherein A is NR.3. The compound of claim 1 , wherein X is —(C-C)-alkyl.4. The compound of claim 1 , wherein{'sup': '4', 'A is NR;'}V is a bond or C(O);{'sup': '13', 'W is a bond or NR;'}{'sub': 1', '3, 'X is —(C-C)-alkyl;'}{'sup': '5', 'Y is NR;'}{'sup': '1', 'sub': 1', '3, 'Ris halogen or —(C-C)-haloalkyl;'}{'sup': 2', '6, 'Ris —OR;'}{'sup': '3', 'Ris —CN or halogen;'}{'sup': 5', '7, 'sub': 1', '3', '1', '3, 'Ris hydrogen, —(C-C)-alkyl, —(C-C)-cycloalkyl, or —C(O)R;'}{'sup': '6', 'sub': 1', '3', '1', '3, 'Ris —(C-C)-alkyl or —(C-C)-haloalkyl;'}{'sup': '7', 'sub': 1', '3, 'Ris —(C-C)-alkyl;'}{'sup': '8', 'sub': 1', '3, 'Ris hydrogen or —(C-C)-alkyl;'}{'sup': '13', 'sub': 1', '3, 'Ris hydrogen or —(C-C)-alkyl; and'}m and n are independently 0, 1 or 2, provided that the sum of m+n is an integer from 2-3.5. The compound of claim 1 , whereinA is NH;V is a bond or C(O);{'sup': '13', 'W is a bond or NR;'}{'sub': 1', '3, 'X is —(C-C)-alkyl;'}{'sup': '5', 'Y is NR;'}{'sup': '1', 'Ris halogen;'}{'sup': 2', '6, 'Ris —OR;'}{'sup': '3', 'Ris —CN or halogen;'}{'sup': 5', '7, 'sub': 1', '3, 'Ris hydrogen, —(C-C)-alkyl, or —C(O)R;'}{'sup': '6', 'sub': 1', '3, 'Ris —(C-C)-alkyl;'}{'sup': '7', 'sub': 1', '3, 'Ris —(C-C)-alkyl;'}{'sup': '8', 'sub': 1', ...

ALDOSE REDUCTASE INHIBITORS AND METHODS OF USE THEREOF

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like. 2. The compound of claim 1 , wherein{'sup': '2', 'sub': 1', '6, 'Ris hydrogen or (C-C)-alkyl;'}Y is C═O;{'sup': 1', '7, 'Ais NR, O, or S;'}{'sup': '2', 'Ais N;'}{'sup': '3', 'Ais O, or S; and'}{'sup': 3', '6, 'sub': 1', '4', '1', '4', '1', '4', '1', '4', '1', '4, 'Rthrough Rare independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl, or (C-C)-alkylsulfonyl;'}or a pharmaceutically acceptable salt or solvate thereof.4. The compound of claim 3 , wherein{'sup': '2', 'sub': 1', '6, 'Ris hydrogen or (C-C)-alkyl;'}Y is C═O;{'sup': 1', '7, 'Ais NR, O, or S;'}{'sup': '2', 'Ais N;'}{'sup': 3', '6, 'sub': 1', '4', '1', '4', '1', '4', '1', '4', '1', '4, 'Rthrough Rare independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C-C)-alkyl, (C-C)-alkoxy, (C-C)-alkylthio, (C-C)-alkylsulfinyl, or (C-C)-alkylsulfonyl; and'}{'sup': '7', 'sub': 1', '4', '1', '4, 'Ris hydrogen, C-Calkyl, or C(O)O—(C-C)-alkyl; or a pharmaceutically acceptable salt or solvate thereof.'}5. The compound of claim 1 , wherein{'sup': '2', 'Ris ...

POTENT NON-UREA INHIBITORS OF SOLUBLE EPOXIDE HYDROLASE

The present invention relates to compounds that exhibit vasodilatory and anti-inflammatory effects by inhibiting the activity of soluble epoxide hydrolase (sEH). The present invention is also directed to methods of identifying such compounds, and use of such compounds for the treatment of diseases related to dysfunction of vasodilation, inflammation, and/or endothelial cells. In particular non-limiting embodiments, components of the invention may be used to treat hypertension. 2. The compound of claim 1 , wherein Ris selected from the group consisting of substituted cycloalkyl claim 1 , unsubstituted cycloalkyl claim 1 , substituted alkyl claim 1 , unsubstituted naphthyl claim 1 , and substituted aryl.8. The method of claim 6 , wherein the inhibition of soluble epoxide hydrolase reduces the metabolism of an epoxyeicosatrienoic acid.9. The method of claim 6 , wherein the soluble epoxide hydrolase is expressed by a cell.10. The method of claim 9 , wherein the cell is a mammalian cell.11. The method of claim 6 , wherein the soluble epoxide hydrolase and compound of Formula I are contacted in vitro.16. The method of claim 14 , wherein the disease is hypertension.19. The method of claim 14 , wherein the compound is administered to the individual at a dosage effective to achieve a serum concentration of between 0.01 nM and 2 μM.20. The method of claim 14 , wherein the compound is administered to the individual in an amount effective to inhibit the in vitro activity of sEH by at least 5-10%.21. The method of claim 14 , wherein the compound administered to the individual has an ICof between 200 nM and 0.01 nM. This application is a continuation of International Application No. PCT/US13/023,008, filed Jan. 24, 2013, which claims the benefit of and priority to U.S. Provisional Application Ser. No. 61/590,701, filed Jan. 25, 2012; U.S. Provisional Application Ser. No. 61/590,792, filed Jan. 25, 2012; and U.S. Provisional Application Ser. No. 61/650,950, filed May 23, 2012; ...

HISTONE ACETYLTRANSFERASE MODULATORS AND USES THEREOF

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels and/or accumulations of alpha-synuclein as well as cancer by administering a compound hat modulates HAT to a subject. 2. The method of claim 1 , wherein the effective amount is at least about 1 mg/kg body weight claim 1 , at least about 2 mg/kg body weight claim 1 , at least about 3 mg/kg body weight claim 1 , at least about 4 mg/kg body weight claim 1 , at least about 5 mg/kg body weight claim 1 , at least about 6 mg/kg body weight claim 1 , at least about 7 mg/kg body weight claim 1 , at least about 8 mg/kg body weight claim 1 , at least about 9 mg/kg body weight claim 1 , at least about 10 mg/kg body weight claim 1 , at least about 15 mg/kg body weight claim 1 , at least about 20 mg/kg body weight claim 1 , at least about 25 mg/kg body weight claim 1 , at least about 30 mg/kg body weight claim 1 , at least about 40 mg/kg body weight claim 1 , at least about 50 mg/kg body weight claim 1 , at least about 75 mg/kg body weight claim 1 , or at least about 100 mg/kg body weight.3. The method of claim 1 , wherein the cancer comprises B cell lymphoma claim 1 , colon cancer claim 1 , lung cancer claim 1 , renal cancer claim 1 , bladder cancer claim 1 , T cell lymphoma claim 1 , myeloma claim 1 , leukemia claim 1 , chronic myeloid leukemia claim 1 , acute myeloid leukemia claim 1 , chronic lymphocytic leukemia claim 1 , acute lymphocytic leukemia claim 1 , hematopoietic neoplasias claim 1 , thymoma claim 1 , lymphoma claim 1 , sarcoma claim 1 , lung cancer claim 1 , liver cancer claim 1 , non-Hodgkins lymphoma claim 1 , Hodgkins lymphoma claim 1 , uterine cancer claim 1 , renal cell carcinoma claim 1 , hepatoma claim 1 , adenocarcinoma claim 1 , breast cancer claim 1 , pancreatic cancer ...

Thermostabilization of proteins

Provided are compositions comprising a cocaine esterase (CocE) and a compound that thermostabilizes the CocE. Also provided are methods of thermostabilizing a cocaine esterase. Additionally provided are methods of treating a mammal undergoing a cocaine-induced condition. Methods of determining whether a compound is a thermostabilizing agent for a protein are also provided. Uses of the above-described compositions for the treatment of a cocaine-induced condition is additionally provided. Additionally provided is an isolated nucleic acid encoding a CocE polypeptide having the substitutions L169K and G173Q, and the CocE polypeptide encoded by that nucleic acid, and pharmaceutical compositions thereof. Further provided is the use of that composition for the manufacture of a medicament for the treatment of a cocaine-induced condition and for the treatment of a cocaine-induced condition.

Potent non-urea inhibitors of soluble epoxide hydrolase

The present invention relates to compounds that exhibit vasodilatory and anti-inflammatory effects by inhibiting the activity of soluble epoxide hydrolase (sEH). The present invention is also directed to methods of identifying such compounds, and use of such compounds for the treatment of diseases related to dysfunction of vasodilation, inflammation, and/or endothelial cells. In particular non-limiting embodiments, components of the invention may be used to treat hypertension.

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The method of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The method of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.7. The method of claim 1 , wherein the cardiovascular disorder is atherosclerosis claim 1 , coronary artery disease claim 1 , peripheral vascular disease or stroke.8. The method of claim 4 , wherein the cardiovascular disorder is atherosclerosis claim 4 , coronary artery disease claim 4 , peripheral vascular disease or stroke.9. The method of claim 5 , wherein the cardiovascular disorder is atherosclerosis claim 5 , coronary artery disease claim 5 , peripheral vascular disease or stroke.10. The method of claim 6 , wherein the cardiovascular disorder is atherosclerosis claim 6 , coronary artery disease claim 6 , peripheral vascular disease or stroke.11. The method of claim 1 , wherein the subject is a human.12. The method of claim 4 , wherein the ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The method of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The method of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.7. The method of claim 1 , wherein the complication of diabetes is diabetic nephropathy claim 1 , diabetic neuropathy or diabetic retinopathy.8. The method of claim 4 , wherein the complication of diabetes is diabetic nephropathy claim 4 , diabetic neuropathy or diabetic retinopathy.9. The method of claim 5 , wherein the complication of diabetes is diabetic nephropathy claim 5 , diabetic neuropathy or diabetic retinopathy.10. The method of claim 6 , wherein the complication of diabetes is diabetic nephropathy claim 6 , diabetic neuropathy or diabetic retinopathy.11. The method of claim 1 , wherein the subject is a human.12. The method of claim 4 , wherein the subject is a human.13. The method of claim 5 , wherein the subject is a human.14. The ...

Aldose reductase inhibitors and methods of use thereof

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

NEURONAL PAIN PATHWAY

The present invention relates to the discovery of a novel molecular pathway involved in long-term hyperexcitability of sensory neurons, which, in higher animals, is associated with persistent pain. It is based on the discovery that, following injury to an axon of a neuron, an increase in nitric oxide synthase activity results in increased nitric oxide production, which, in turn, activates guanylyl cyclase, thereby increasing levels of cGMP. Increased cGMP results in activation of protein kinase G (“PKG”), which then is retrogradely transported along the axon to the neuron cell body, where it phosphorylates MAPKerk. 2. The transdermal device of claim 1 , wherein the agent is balanol.3. The transdermal device of claim 1 , wherein the agent is a balanol variant.4. The transdermal device of claim 3 , wherein the balanol variant is selected from the group consisting of balanol-7R claim 3 , 14-decarboxy-balanol claim 3 , 10-deoxy-balanol claim 3 , balanol linked to a transport peptide claim 3 , a balanol variant linked to a transport peptide claim 3 , balanol linked to a carrier peptide claim 3 , a balanol variant linked to a carrier peptide claim 3 , balanol linked to a transport peptide and a carrier peptide claim 3 , and a balanol variant linked to a transport peptide and a carrier peptide.5. The transdermal device of claim 1 , wherein the compound of formula I is linked to a transport peptide.6. The transdermal device of claim 2 , wherein the compound of formula I is linked to a transport peptide.7. The transdermal device of claim 3 , wherein the compound of formula I is linked to a transport peptide.8. The transdermal device of claim 4 , wherein the compound of formula I is linked to a transport peptide. The present application is a divisional application of U.S. patent application Ser. No. 13/569,510 filed on Aug. 8, 2012, which is a divisional of U.S. patent application Ser. No. 11/385,455, filed on Mar. 21, 2006 (issued as U.S. Pat. No. 8,252,754 on Aug. 28, 2012 ...

Potent non-urea inhibitors of soluble epoxide hydrolase

The present invention relates to compounds that exhibit vasodilatory and anti-inflammatory effects by inhibiting the activity of soluble epoxide hydrolase (sEH). The present invention is also directed to methods of identifying such compounds, and use of such compounds for the treatment of diseases related to dysfunction of vasodilation, inflammation, and/or endothelial cells. In particular non-limiting embodiments, components of the invention may be used to treat hypertension.

ALDOSE REDUCTASE INHIBITORS AND METHODS OF USE THEREOF

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like. 2. The compound of claim 1 , wherein{'sup': '2', 'sub': 1', '6, 'Ris (C-C)-alkyl.'}320.-. (canceled)21. The compound of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.22. The compound of claim 1 , wherein Ris (C-C)-hydroxyalkyl.23. The compound of claim 22 , wherein Rthrough Rare independently hydrogen claim 22 , halogen claim 22 , or haloalkyl.24. The compound of claim 1 , wherein Ris (C-C)-aminoalkyl.25. The compound of claim 24 , wherein Rthrough Rare independently hydrogen claim 24 , halogen claim 24 , or haloalkyl.26. The compound of claim 1 , wherein Ris H.27. The compound of claim 26 , wherein Rthrough Rare independently hydrogen claim 26 , halogen claim 26 , or haloalkyl.28. The compound of claim 1 , wherein R claim 1 , Rand Rare each hydrogen; and Ris hydrogen claim 1 , halogen claim 1 , or haloalkyl.29. The compound of claim 2 , wherein R claim 2 , Rand Rare each hydrogen; and Ris hydrogen claim 2 , halogen claim 2 , or haloalkyl.30. The compound of claim 22 , wherein R claim 22 , Rand Rare each hydrogen; and Ris hydrogen claim 22 , halogen claim 22 , or ...

ALDOSE REDUCTASE INHIBITORS AND USES THEREOF

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like. 2. The compound of claim 1 , wherein Y is C═O; and Rthrough Rare independently hydrogen claim 1 , halogen claim 1 , cyano claim 1 , acyl claim 1 , haloalkyl claim 1 , haloalkoxy claim 1 , haloalkylthio claim 1 , (C-C)-alkyl claim 1 , (C-C)-alkoxy claim 1 , (C-C)-alkylthio claim 1 , (C-C)-alkylsulfinyl claim 1 , or (C-C)-alkylsulfonyl.3. The compound of claim 2 , wherein Rthrough Rare independently hydrogen claim 2 , halogen claim 2 , or haloalkyl.4. The compound of claim 2 , wherein R claim 2 , Rand Rare hydrogen; and Ris hydrogen claim 2 , halogen or haloalkyl.5. The compound of claim 1 , wherein Ris ethyl or tert-butyl.10. A pharmaceutical composition comprising the compound of and a pharmaceutically acceptable carrier.11. A method of inhibiting aldose reductase comprising administering to a subject in need thereof an effective amount of a compound of .12. The method of claim 11 , wherein the subject has a complication of diabetes.13. The method of claim 12 , wherein the complication of diabetes is diabetic nephropathy claim 12 , diabetic neuropathy or diabetic retinopathy.14. The method of claim 11 , wherein the subject has a cardiovascular disorder.15. The method of claim 14 , ...

ANTI-DRUG VACCINES

The present invention relates to anti-drug vaccines based on conjugates between the drug and a non-immunogenic carrier protein. In preferred embodiments, it provides for anti-cocaine vaccines and their use to diminish the effects and/or use of cocaine in a subject. 1. A pharmaceutical composition comprising a drug/Self protein conjugate , in an amount effective at inducing an immune response to the drug in an immunocompetent subject , together with a suitable pharmaceutical carrier , where the Self protein is not immunogenic in said subject.2. The pharmaceutical composition of claim 1 , wherein the drug is cocaine.3. The pharmaceutical composition of claim 1 , wherein the Self protein is a human immunoglobulin.4. The pharmaceutical composition of claim 1 , which further comprises an adjuvant.5. A pharmaceutical composition comprising a conjugate between a Self protein and a hapten selected from the group consisting of cocaine claim 1 , a cocaine derivative claim 1 , and a transition state analog of cocaine claim 1 , in an amount effective at inducing an immune response to cocaine in an immunocompetent subject claim 1 , together with a suitable pharmaceutical carrier claim 1 , where the Self protein is not immunogenic in said subject.6. The pharmaceutical composition of claim 5 , wherein the Self protein is a human immunoglobulin.7. The pharmaceutical composition of claim 5 , which further comprises an adjuvant.9. A conjugate formed between a cocaine pre-hapten of claim 8 , and a serum protein.10. The conjugate of claim 9 , wherein the serum protein is a human immunoglobulin.11. A pharmaceutical composition comprising the conjugate of claim 9 , in a suitable pharmaceutical carrier.12. The pharmaceutical composition of claim 11 , wherein the conjugate is present in an amount effective at inducing an immune response to the drug in an immunocompetent subject claim 11 , together with a suitable pharmaceutical carrier claim 11 , where the serum protein is not immunogenic ...

HISTONE ACETYLTRANSFERASE ACTIVATORS AND COMPOSITIONS AND USES THEREOF

The invention provides pharmaceutical compositions and methods for treating cancer, neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein by administering a HAT modulator and a HDAC modulator to a subject. 5. The method of claim 1 , wherein the cancer comprises B cell lymphoma claim 1 , colon cancer claim 1 , lung cancer claim 1 , renal cancer claim 1 , bladder cancer claim 1 , T cell lymphoma claim 1 , myeloma claim 1 , leukemia claim 1 , chronic myeloid leukemia claim 1 , acute myeloid leukemia claim 1 , chronic lymphocytic leukemia claim 1 , acute lymphocytic leukemia claim 1 , hematopoietic neoplasias claim 1 , thymoma claim 1 , lymphoma claim 1 , sarcoma claim 1 , lung cancer claim 1 , liver cancer claim 1 , non-Hodgkin's lymphoma claim 1 , Hodgkin's lymphoma claim 1 , uterine cancer claim 1 , renal cell carcinoma claim 1 , hepatoma claim 1 , adenocarcinoma claim 1 , breast cancer claim 1 , pancreatic cancer claim 1 , liver cancer claim 1 , prostate cancer claim 1 , head and neck carcinoma claim 1 , thyroid carcinoma claim 1 , soft tissue sarcoma claim 1 , ovarian cancer claim 1 , primary or metastatic melanoma claim 1 , squamous cell carcinoma claim 1 , basal cell carcinoma claim 1 , brain cancer claim 1 , angiosarcoma claim 1 , hemangiosarcoma claim 1 , bone sarcoma claim 1 , fibrosarcoma claim 1 , myxosarcoma claim 1 , liposarcoma claim 1 , chondrosarcoma claim 1 , osteogenic sarcoma claim 1 , chordoma claim 1 , angiosarcoma claim 1 , endotheliosarcoma claim 1 , lymphangiosarcoma claim 1 , lymphangioendotheliosarcoma claim 1 , synovioma claim 1 , testicular cancer claim 1 , uterine cancer claim 1 , cervical cancer claim 1 , gastrointestinal cancer claim 1 , mesothelioma claim 1 , Ewing's tumor claim 1 , leiomyosarcoma claim 1 , rhabdomyosarcoma claim 1 , colon carcinoma claim 1 , pancreatic cancer claim 1 , breast cancer claim 1 , ovarian cancer claim 1 , ...

Histone Acetyltransferase Activators and Uses Thereof

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject. 3. The compound of claim 1 , wherein{'sup': '1', 'sub': 1', '6', '1', '6', '1', '6', '1', '6, 'Ris OH, C-C-alkyl, C-C-haloalkyl, —O—(C-C-alkyl), or —O—(C-C-haloalkyl); and'}{'sup': 2', '5', '5', '+', '5', '5, 'sub': 2', '6', '2', '2', '6', '3', '2', '6', '2', '1', '6, 'Ris OH, —O—(C-C-alkyl)-N(R), —O—(C-C-alkyl)-N(R)halogen-, —N(R)—(C-C-alkyl)-N(R), or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '2', '6', '3, 'wherein when Ris OH, Ris OH, —O—(C-C-alkyl)-phenyl, or —O—(C-C-alkyl)-N(R)halogen;'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '1', '6', '2', '6', '3, 'when Ris C-C-alkyl, Ris —O—(C-C-alkyl)-phenyl or —O—(C-C-alkyl)-N(R)halogen;'}{'sup': 1', '2', '5', '+, 'sub': 1', '6', '2', '6', '3', '1', '6, 'when Ris —O—(C-C-alkyl), Ris halogen, —O—(C-C-alkyl)-N(R)halogen- or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2, 'and wherein Rand Rare not both H.'}4. The compound of claim 3 , wherein{'sup': '1', 'sub': 1', '6, 'Ris OH, or C-C-alkyl; and'}{'sup': 2', '5', '+, 'sub': 2', '6', '3', '1', '6, 'Ris OH, —O—(C-C-alkyl)-N(R)halogen-, or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '2', '6', '3, 'wherein when Ris OH, Ris OH, —O—(C-C-alkyl)-phenyl, or —O—(C-C-alkyl)-N(R)halogen; and'}{'sup': 1', '2', '5', '+', '−, 'sub': 1', '6', '1', '6', '2', '6', '3, 'when Ris C-C-alkyl, Ris OH, —O—(C-C-alkyl)-phenyl, or —O—(C-C-alkyl)-N(R)halogen.'}5. The compound of claim 4 , wherein{'sup': '1', 'sub': 1', '2, 'Ris OH, or C-C-alkyl; and'}{'sup': '2', 'sub': 1', '3, 'Ris OH, or —O—(C-C-alkyl)-phenyl;'}{'sup': 1', '2, 'sub': 1', '3, ' ...

Selective capture and release of analytes

The described subject matter includes techniques and components for minimally invasive, selective capture and release of analytes. An aptamer is selected for its binding affinity with a particular analyte(s). The aptamer is functionalized on a solid phase, for example, microbeads, polymer monolith, microfabricated solid phase, etc. The analyte is allowed to bind to the aptamer, for example, in a microchamber. Once the analyte has been bound, a temperature control sets the temperature to an appropriate temperature at which the captured analyte is released.

Phosphodiesterase inhibitors and uses thereof

Phosphodiesterase inhibitors and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention further provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

Histone acetyltransferase activators and uses thereof

Histone acetyltransferase activators and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject.

Histone acetyltransferase modulators and their uses

Compuesto de fórmula (I): **(Ver fórmula)** en la que **(Ver fórmula)** Ar es Ra es halógeno o haloalquilo; Rb es O-(alquil C2-C4), O-(cicloalquil C3-C5), N(R10)-(alquil C1-C4) o N(R10)-(cicloalquil C3-C5); Rc es H; Rd es O-(alquil C2-C4)-N(R10)2, -(alquil C1-C4)-R3, O-(alquil C1-C4)-R3 o -(alquil C1-C4)-N(R10)2; W y Z son cada uno CH; X es -CON(R10)-; Y es CR2; R2 es halógeno o haloalquilo; R3 es cicloalquil C3-C8-amino, morpolinilo, tiomorfolinilo o N-alquilpiperazinilo; y R10 es independientemente H o -(alquil C1-C2), n es un número entero desde 1-3, **(Ver fórmula)** con la condición de que el compuesto no sea **(Ver fórmula)** Compound of formula (I): ** (See formula) ** wherein ** (See formula) ** Ar is Ra is halogen or haloalkyl; Rb is O- (C2-C4 alkyl), O- (C3-C5 cycloalkyl), N (R10) - (C1-C4 alkyl) or N (R10) - (C3-C5 cycloalkyl); Rc is H; Rd is O- (C2-C4 alkyl) -N (R10) 2, - (C1-C4 alkyl) -R3, O- (C1-C4 alkyl) -R3 or - (C1-C4 alkyl) -N (R10) two; W and Z are each CH; X is -CON (R10) -; Y is CR2; R2 is halogen or haloalkyl; R3 is C3-C8 cycloalkyl-amino, morpolinyl, thiomorpholinyl, or N-alkylpiperazinyl; and R10 is independently H or - (C1-C2 alkyl), n is an integer from 1-3, ** (See formula) ** provided the compound is not ** (See formula) **

Aldose reductase inhibitors and uses thereof

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Aldose reductase inhibitors and methods of use thereof.

La presente divulgación se refiere a nuevos compuestos y composiciones farmacéuticas de los mismos, así como a métodos para favorecer el envejecimiento saludable de la piel, el tratamiento de trastornos de la piel, el tratamiento de enfermedades cardiovasculares, el tratamiento de trastornos renales, el tratamiento de trastornos relacionados con la angiogénesis, como el cáncer, el tratamiento de lesiones tisulares, como danos a los tejidos no cardiacos, el tratamiento del infarto de miocardio en evolución, el tratamiento de la lesión isquémica y el tratamiento de varios otros trastornos, como las complicaciones derivadas de la diabetes, por medio de los compuestos y composiciones de la invención. Otros trastornos pueden incluir, de manera enunciativa mas no limitativa, ateroesclerosis, enfermedad coronaria, nefropatía diabética, neuropatía diabética, retinopatía diabética, cardiomiopatía diabética, infecciones de la piel, enfermedad vascular periférica, accidente cerebrovascular, asma, y otros similares.

Phosphodiesterase inhibitors and uses thereof

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

Histone acetyltransferase modulators and uses thereof

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

Histone acetyltransferase activators and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject.

Phosphodiesterase inhibitors and uses thereof

The invention provides for compounds that are phosphodiesterase inhibitors. The invention further provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention also provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

Histone acetyltransferase activators and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject.

Histone acetyltransferase activators and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a histone acetyltransferase protein. The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a HAT-activating compound to a subject.

Phosphodiesterase inhibitors and uses thereof

The invention provides for a method for screening compounds that bind to and modulate a phosphosdiesterase protein. The invention further provides methods for treating conditions associated with accumulated amyloid-beta peptide deposit accumulations by administering a phosphodiesterase-binding compound to a subject.

Benzothiazepine derivatives as ryanodine receptor (RYR2) inhibitors and their use in the treatment of cardiac diseases

The present invention provides methods for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject. The present invention further provides methods for treating and preventing atrial and ventricular cardiac arrhythmias, heart failure, and exercise-induced sudden cardiac death in a subject. Additionally, the present invention provides use of JTV-519 in a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject who has, or is a candidate for, atrial fibrillation. Also provided are uses of 1,4-benzothiazepine derivatives in methods for treating and preventing atrial and ventricular cardiac arrhythmias and heart failure in a subject, and for preventing exercise-induced sudden cardiac death. The present invention also provides methods for identifying agents for use in treating and preventing atrial fibrillation and heart failure, and agents identified by these methods. To be accompanied, when published, by Figure 1 of the drawings.

Anti-cocaine catalytic antibody

Disclosed are catalytic antibodies and polypeptides capable of degrading cocaine. Said catalytic antibodies and polypeptides are characterized by the amino acid sequence of their complementarity determining regions and framework regions. The present invention also discloses a pharmaceutical composition and a method for decreasing the concentration of cocaine in a subject. Finally, the invention discloses pharmaceutical compositions and methods for treating cocaine overdose and addiction in subjects.

Methods, systems, and media for controlling access to applications on mobile devices

Methods, systems, and media for controlling access to applications on mobile devices are provided. In accordance with some embodiments, a method for controlling access to mobile device applications is provided, the method comprising: receiving a presentation for distribution to a plurality of mobile devices, wherein at least one task is associated with the presentation and control information for controlling access to applications installed on each of the plurality of mobile devices is associated with the presentation; transmitting the presentation to the plurality of mobile devices; determining whether each of the plurality of mobile devices performed the at least one task associated with the presentation; and, in response to determining that a mobile device has not performed the at least one task, using the control information to disable at least one application installed on the mobile device.

Aldose reductase inhibitors and uses thereof

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Aldose reductase inhibitors and methods of use thereof

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.

Aldose reductase inhibitors and uses thereof

Aldose reductase inhibitors and uses thereof

Histone acetyltransferase activators and uses thereof

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

Histone acetyltransferase modulators and compositions and uses thereof

Compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.

Inhibitors of central nervous system vasoactive inhibitory peptide receptor 2

The present invention relates to compounds that inhibit VIPR2 in the CNS, pharmaceutical compositions comprising said compounds, and methods of using such compounds and compositions in the treatment of a CNS disorder such as a behavioral disorder, including but not limited to schizophrenia.

Neuronal pain pathway

The present invention relates to the discovery of a novel molecular pathway involved in long-term hyperexcitability of sensory neurons, which, in higher animals, is associated with persistent pain. It is based on the discovery that, following injury to an axon of a neuron, an increase in nitric oxide synthase activity results in increased nitric oxide production, which, in turn, activates guanylyl cyclase, thereby increasing levels of cGMP. Increased cGMP results in activation of protein kinase G (“PKG”), which then is retrogradely transported along the axon to the neuron cell body, where it phosphorylates MAPKerk.

New neuronal pain pathway

Histone acetyltransferase modulators and uses thereof

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject. In one aspect the compound might be a compound of formula (I): (see formula I)

Androgen activity antagonists as therapies for anorexia, anorexia nervosa, and disorders characterized by a pathologically underweight condition

The present invention relates to the treatment of conditions characterized by loss of appetite (anorexia) and/or pathological weight loss by administering a therapeutically effective amount of an agent that modulates androgen activity. The present invention further relates to the treatment and prevention of anorexia nervosa with such agents.

Agents for preventing and treating disorders involving modulation of the ryr receptors

The present invention provides compounds of Formula I, (I) and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells.

Use of optically pure (R)-tofisopam for treating and preventing anxiety disorders.

Agents for preventing and treating disorders involving modulation of the ryr receptors

COMPOUNDS AND METHODS FOR TREATMENT AND PREVENTION OF CARDIAC ARRHYTHMIES INDUCED BY PHYSICAL EXERCISE

Cette invention concerne un procédé visant à limiter ou à prévenir une baisse du niveau de protéines FKBP12.6 liées à RyR2 chez un sujet, une méthode de traitement ou de prévention de l'arythmie cardiaque induite par l'exercice physique chez un sujet, ainsi qu'une méthode de prévention de la mort cardiaque subite induite par l'exercice physique chez un sujet. Cette invention concerne également les utilisations de JTV-519 dans ces méthodes. Cette invention concerne en outre des méthodes permettant d'identifier des agents utilisés pour prévenir la mort cardiaque subite induite par l'exercice physique, ainsi que les agents identifiés par ces méthodes. Cette invention concerne par ailleurs des méthodes de prévention de la mort cardiaque subite induite par l'exercice physique consistant à administrer ces agents. En outre, cette invention concerne des méthodes permettant de synthétiser le JTV-519, le JTV-519 radio marqué et des intermédiaires et dérivés de la 1,4-benzothiazépine. The present invention provides a method for limiting or preventing a decrease in the level of RyR2-related FKBP12.6 proteins in a subject, a method of treating or preventing exercise-induced cardiac arrhythmia in a subject, and that a method of preventing sudden cardiac death induced by physical exercise in a subject. This invention also relates to the uses of JTV-519 in these methods. The invention further provides methods for identifying agents used to prevent exercise-induced sudden cardiac death, as well as agents identified by these methods. The present invention further provides methods of preventing exercise-induced sudden cardiac death by administering these agents. In addition, this invention provides methods for synthesizing JTV-519, labeled radio-labeled JTV-519, and 1,4-benzothiazepine intermediates and derivatives.

Aldose reductase inhibitors and uses thereof

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Aldose reductase inhibitors and methods of use thereof

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.

Aldose reductase inhibitors and methods of use thereof

Thermostabilization of proteins

Provided are compositions comprising a cocaine esterase (CocE) and a compound that thermostabilizes the CocE. Also provided are methods of thermostabilizing a cocaine esterase. Additionally provided are methods of treating a mammal under-going a cocaine-induced condition. Methods of determining whether a compound is a thermostabilizing agent for a protein are also provided. Uses of the above-described compositions for the treatment of a cocaine-induced condition is additionally provided. Additionally provided is an isolated nucleic acid encoding a CocE polypeptide having the substitutions L169K and G173Q, and the CocE polypeptide encoded by that nucleic acid, and pharmaceutical compositions thereof. Further provided is the use of that composition for the manufacture of a medicament for the treatment of a cocaine-induced condition and for the treatment of a cocaine-induced condition.

A method for stabilizing blood pressure in hemodialysis subjects

The present invention provides a method for regulating blood pressure in a hemodialysis subject using a vasopressin receptor agonist, so as to facilitate removal of excessive extracellular fluid in the subject.

Androgen activity antagonists as therapies for anorexia, anorexia nervosa, and disorders characterized by a pathologically underweight condition

Agents for preventing and treating disorders involving modulation of the ryr receptors

The present invention provides compounds of Formula I, (I) and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells.

Androgen activity antagonists as therapies for anorexia, anorexia nervosa, and disorders characterized by a pathologically underweight condition

The present invention relates to the treatment of conditions characterized by loss of appetite (anorexia) and/or pathological weight loss by administering a therapeutically effective amount of an agent that modulates androgen activity. The present invention further relates to the treatment and prevention of anorexia nervosa with such agents.

Anti-drug vaccines

The present invention relates to anti-drug vaccines based on conjugates between the drug and a non-immunogenic carrier protein. In preferred embodiments, it provides for anti-cocaine vaccines and their use to diminish the effects and/or use of cocaine in a subject.

Agents for preventing and treating disorders involving modulation of the ryr receptors

Novel anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (ryr2)

The present invention provides novel 1,4-benzothiazepine intermediates and derivatives, methods for synthesizing same, and methods for assaying same. The present invention also provides methods for using these novel compounds to limit or prevent a decrease in the level of RyR2-bound FKBP12.6 in a subject; to prevent exercise-induced sudden cardiac death in a subject; and to treat or prevent heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia in a subject. The present invention further provides methods for identifying an agent that enhances binding of RyR2 and FKBP12.6, and agents identified by these methods. Additionally, the present invention provides methods for identifying agents for use in treating or preventing heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia, and in preventing exercise-induced sudden cardiac death. Also provided are agents identified by such methods.

Potent non-urea inhibitors of soluble epoxide hydrolase

The present invention relates to compounds that exhibit vasodilatory and anti-inflammatory effects by inhibiting the activity of soluble epoxide hydrolase (sEH). The present invention is also directed to methods of identifying such compounds, and use of such compounds for the treatment of diseases related to dysfunction of vasodilation, inflammation, and/or endothelial cells. In particular non-limiting embodiments, components of the invention may be used to treat hypertension.

Histone acetyltransferase modulators and compositions and uses thereof

Compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject.