Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective 尾3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder

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• 作者：Christopher R. Moyes ; Richard Berger ; Stephen D. Goble ; Bart Harper ; Dong-Ming Shen ; Liping Wang ; Alka Bansal ; Patricia N. Brown ; Airu S. Chen ; Karen H. Dingley ; Jerry Di Salvo ; Aileen Fitzmaurice ; Loise N. Gichuru ; Amanda L. Hurley ; Nina Jochnowitz ; Randall R. Miller ; Shruty Mistry ; Hiroshi Nagabukuro ; Gino M. Salituro ; Anthony Sanfiz ; Andra S. Stevenson ; Katherine Villa ; Beata Zamlynny ; Mary Struthers ; Ann E. Weber ; Scott D. Edmondson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1437-1453
• 全文大小：531K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

A series of conformationally restricted acetanilides were synthesized and evaluated as 尾₃-adrenergic receptor agonists (尾₃-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine 尾₃-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent 尾₃-AR mediated responses in a rat bladder hyperactivity model.