Structure-Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

详细信息    查看全文

• 作者：Arturo Perez-Medrano ; Michael E. Brune ; Steven A. Buckner ; Michael J. Coghlan ; Thomas A. Fey ; Murali Gopalakrishnan ; Robert J. Gregg ; Michael E. Kort ; Victoria E. Scott ; James P. Sullivan ; Kristi L. W
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6265 - 6273
• 全文大小：103K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substitutedbenzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarizedhuman bladder cells as assessed by the FLIPR membrane potential dye (K_ATP-FMP). These compoundswere also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model ofoveractive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pigmodel of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oralbioavailability and a t_1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents arediscussed.