- HETEROARYL-SUBSTITUTED SULFONAMIDE COMPOUNDS AND THEIR USE AS SODIUM CHANNEL INHIBITORS
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This invention is directed to heteroaryl-substituted sulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.
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- Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists
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A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC50 values (0.27–1.2 μM) though they appeared to be partial agonists.
- Fang, Yuanying,Xiong, Lijuan,Hu, Jianguo,Zhang, Shaokun,Xie, Saisai,Tu, Liangxing,Wan, Yang,Jin, Yi,Li, Xiang,Hu, Shaojie,Yang, Zunhua
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p. 103 - 111
(2019/01/28)
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- Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as GPR119 agonist for treatment of type 2 diabetes
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We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg.
- Fang, Yuanying,Xu, Jun,Li, Zhifeng,Yang, Zunhua,Xiong, Lijuan,Jin, Yi,Wang, Qi,Xie, Saisai,Zhu, Wufu,Chang, Sheng
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p. 4080 - 4087
(2018/07/02)
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- 8-AZABICYCLO[3.2.1]OCTANE-8-CARBOXAMIDE DERIVATIVE
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Disclosed is a compound represented by formula (1) or a pharmacologically acceptable salt thereof (In the formula, A represents a group that is represented by formula (A-1); R1a and R1b may be the same or different and each independently represents a C1-6 alkyl group which may be substituted by one to three halogen atoms; m and n each independently represents an integer of 0-5; X1 represents a hydroxyl group or an aminocarbonyl group; Z1 represents a single bond or the like; and R2 represents an optionally substituted C1-6 alkyl group, an optionally substituted C6-10 aryl group or the like.)
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Page/Page column 29
(2012/09/11)
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- An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: The discovery of N -{(1 S)-1-(3-fluorophenyl)-3-[(3- endo)-3-(5-isobutyryl-2- methyl-4,5,6,7-tetrahydro-1 H -imidazo[4,5- c ]pyridin-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]propyl}acetamide (PF-232798)
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Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
- Stupple, Paul A.,Batchelor, David V.,Corless, Martin,Dorr, Patrick K.,Ellis, David,Fenwick, David R.,Galan, Sébastien R. G.,Jones, Rhys M.,Mason, Helen J.,Middleton, Donald S.,Perros, Manos,Perruccio, Francesca,Platts, Michelle Y.,Pryde, David C.,Rodrigues, Deborah,Smith, Nicholas N.,Stephenson, Peter T.,Webster, Robert,Westby, Mike,Wood, Anthony
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- NOVEL HETEROCYCLIC CARBOXAMIDES AS M1 AGONISTS
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The present invention relates to novel M1 agonistic compounds of formula (I) and their use in the treatment of cognitive impairment associated i.a. with schizophrenia and in the treatment of other diseases mediated by the muscarinic M1 receptor.
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- Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives
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The optimization of a series of 1-aryl-3-piperidinyl urea derivatives is described in which incorporation of tropenyl and homotropenyl moieties has led to significant improvements in activity and drug-like properties. Replacement of the central piperidine
- Watson, Robert J.,Allen, Daniel R.,Birch, Helen L.,Chapman, Gayle A.,Galvin, Frances C.,Jopling, Louise A.,Knight, Roland L.,Meier, Dorica,Oliver, Kathryn,Meissner, Johannes W.G.,Owen, David A.,Thomas, Elizabeth J.,Tremayne, Neil,Williams, Sophie C.
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p. 147 - 151
(2008/09/17)
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- N-ALKYL-AZACYCLOALKYL NMDA/NR2B ANTAGONISTS
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Compounds represented by Formula (I): and/or pharmaceutically acceptable salts, individual enantiomers and stereoisomers thereof, are effective as NMDA/NR2B antagonists useful for treating conditions such as pain, Parkinson’s disease, Alzheimer’s disease, epilepsy, depression, anxiety, ischemic brain injury including stroke.
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- Quinolinone compounds as 5-HT4 receptor agonists
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The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 23-24
(2008/06/13)
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- IMIDAZOPYRIDINE SUBSTITUTED TROPANE DERIVATIVES WITH CCR5 RECEPTOR ANTAGONIST ACTIVITY FOR THE TREATMENT OF HIV AND INFLAMMATION
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The present invention provides compounds of formula (I) wherein R1 and R2 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
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Page/Page column 39
(2010/02/11)
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- Tropane derivatives useful in therapy
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The present invention provides compounds of formula (I) wherein X, Y, R1, R2 and R3 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
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