4-Piperidin-4-ylidenemethyl-benzamides as ¦Ä-opioid receptor agonists for CNS indications: Identifying clinical candidates

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• 作者：Cathy L. Dantzman ; Megan M. King ; Glen E. Ernst ; Xia Wang ; John P. McCauley Jr. ; Donald W. Andisik ; Kelly Brush ; Khanh H. Bui ; William Frietze ; Valerie Hoesch ; Jay Liu ; William E. Palmer ; Nathan Spear ; Thomas J. Hudzik ; Steven S. Wesolowski ; ^{steven.wesolowski@astrazeneca.com}
• 关键词：Delta opioid agonist ; hERG ; P-glycoprotein efflux ; Microsomal clearance
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 January, 2012
• 年：2012
• 卷：22
• 期：2
• 页码：1174-1178
• 全文大小：797 K

文摘

A series of 4-piperidin-4-ylidenemethyl-benzamide ¦Ä-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R¹), the piperidine nitrogen (R²), and the amide (R³). Each region contributes to the balance of properties for ¦Ä opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.