Discovery of N-{4-[(3-Hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide Analogues as Selective Kappa Opioid Receptor Antagonists

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• 作者：Chad M. Kormos ; Chunyang Jin ; Juan Pablo Cueva ; Scott P. Runyon ; James B. Thomas ; Lawrence E. Brieaddy ; S. Wayne Mascarella ; Hern谩n A. Navarro ; Brian P. Gilmour ; F. Ivy Carroll
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4551-4567
• 全文大小：580K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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