192990-05-9Relevant academic research and scientific papers
Synthesis and SAR of thieno[3,2-b]pyridinyl urea derivatives as urotensin-II receptor antagonists
Lim, Chae Jo,Oh, Seung Ae,Lee, Byung Ho,Oh, Kwang-Seok,Yi, Kyu Yang
, p. 5832 - 5835 (2015/01/08)
The preparation and SAR profile of thieno[3,2-b]pyridinyl urea derivatives as novel and potent urotensin-II receptor antagonists are described. An activity optimization study, probing the effects of substituents on thieno[3,2-b]pyridinyl core and benzyl group of the piperidinyl moiety, led to the identification of p-fluorobenzyl substituted thieno[3,2-b]pyridinyl urea 6n as a highly potent UT antagonist with an IC50 value of 13 nM. Although 6n displays good metabolic stability and low hERG binding activity, it has an unacceptable oral bioavailability.
4-hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: A novel, potent, and selective NR1/2B NMDA receptor antagonist
Zhou, Zhang-Lin,Cai, Sui Xiong,Whittemore, Edward R.,Konkoy, Christopher S.,Espitia, Stephen A.,Tran, Minhtam,Rock, David M.,Coughenour, Linda L.,Hawkinson, Jon E.,Boxer, Peter A.,Bigge, Christopher F.,Wise, Lawrence D.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
, p. 2993 - 3000 (2007/10/03)
A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 μM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for α1-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a ~25-fold increase in NR1A/2B potency (IC50 = 0.025 μM). p-Methyl substitution on the benzyl ring (10b) produced a ~3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for α1 receptors and reduction in inhibition of K+ channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4- hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.
Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis and biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines
Wright, Jon L.,Gregory, Tracy F.,Bigge, Christopher F.,Boxer, Peter A.,Serpa, Kevin,Meltzer, Leonard T.,Wise, Lawrence D.,Cai, Sui Xiong,Hawkinson, Jon E.,Konkoy, Christopher S.,Whittemore, Edward R.,Woodward, Richard M.,Zhou, Zhang-Lin
, p. 2469 - 2477 (2007/10/03)
A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing α-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl ? propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.
4-HYDROXY-PIPERODINE DERIVATIVES
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, (2008/06/13)
The present invention relates to compounds of the formula STR1 wherein x is--O--,--NH--,--CH 2--,--CH=,--CO 2--,--CONH--,--CON(lower alkyl)--,--S--and--SO 2--; R. sup.1-R. sup.4 are, independently from each other hydrogen, halogen, hydroxy, amino, nitro, lower-alkyl-sulfonylamido, 1-or 2-imidazolyl, 1-(1,2,4-triazolyl) or acetamido;R 5, R 6 are, independently from each other hydrogen, lower-alkyl, hydroxy, lower alkoxy or oxo;R. sup.7-R 10 are, independently from each other hydrogen, lower-alkyl, halogen, trifluoromethyl or lower-alkoxy;n is 0 or 1; and to pharmaceutically acceptable acid addition salts thereof. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers.
