Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists.

摘要: There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a class In this study, we report syntheses two piperazine JDTic-like analogues. Evaluation compounds an vitro [(35)S]GTPγS binding assay showed neither compound high potency selectivity JDTic. A library using core scaffold 21 was synthesized tested for their ability to inhibit stimulated by selective agonist U69,593. These studies led N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), good antagonist properties. An SAR study based on 11a provided 28 novel these several analogues potent