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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 G1 alpha for imaging the anatomic basis for chronic pain. Such imaging may also be used to objectively quantify chronic pain. Specifically, fluorine-18 and carbon -11 labeled NOP compouds, [18F] NOP46 and [11 C]NOP46, are disclosed for use as imaging agents for detecting and quantifying neuropathic pain.

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A method for inhibiting ROCK compound and its application (by machine translation)

The present invention discloses a compound of the formula I as shown, or a stereoisomer thereof, or a pharmaceutically acceptable salt, or solvate thereof, or prodrug thereof, or its metabolic product. The test shows, the compounds of the invention has good ROCK inhibition activity, can be effectively used for ROCK activity with abnormal in the treatment of diseases. (by machine translation)

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Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11?16) and (indazole-5-yl)methanimines (17?22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson’s disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ¡À 1.7 muM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17?22 as the amide spacer in their carboxamide analogs 11?16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.

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Monoacylglycerol Lipase Modulators

Fused compounds of Formula (I) and Formula (II), pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, bipolar disorder), cancers and eye conditions. Wherein R1, R2, R2a, R3, R3a, R4, and R4a are defined herein.

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Benzothiophene – Wikipedia,
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NOVEL TETRAHYDROPYRIDOPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

The present invention provides novel compounds having the general formula (I) wherein R1, R2 and Z are as described herein, compositions including the compounds and methods of using the compounds.

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Benzothiophene – Wikipedia,
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Structure-activity relationship study of novel NR2B-selective antagonists with arylamides to avoid reactive metabolites formation

A novel potent NMDA-NR2B selective antagonist (5b) without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.

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LINEAR GLYCOSIDASE INHIBITORS

Compounds of formula (I) wherein A, R, W, Q, L, n and m have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer’s disease.

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Discovery of an MLLT1/3 YEATS Domain Chemical Probe

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3?histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.

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Benzothiophene – Wikipedia,
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Design, synthesis, and evaluation of acetylcholinesterase and butyrylcholinesterase dual-target inhibitors against Alzheimer?s diseases

A series of novel compounds 6a?h, 8i?1, 10s?v, and 16a?d were synthesized and evaluated, together with the known analogs 11a?f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 muM) and BChE (eqBChE IC50 = 0.28 muM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer?s disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.

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ARYL-AND HETEROARYLCARBONYL DERIVATIVES OF SUBSTITUTED NORTROPANES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND THEIR USE

The present invention relates to compounds defined by formula (I) wherein the groups R1 and R2 are defined as in claim 1, possessing valuable pharmacological activity. Particularly the compounds are inhibitors of 11 beta-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity, and dyslipidemia

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