Discovery of new piperidine amide triazolobenzodiazepinones as intestinal-selective CCK1 receptor agonists

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• 作者：Kimberly O. Cameron^a ; ^{kimberly.o.cameron@pfizer.com} ; Elena E. Beretta^a ; Yue Chen^b ; Margaret Chu-Moyer^a ; Dilinie Fernando^a ; Hua Gao^a ; Jeffrey Kohrt^a ; Sophie Lavergne^a ; Paul Da Silva Jardine^a ; Angel Guzman-Perez^a ; Christopher Hoth^a ; David A. Perry^a ; John R. Hadcock^a ; Denise Gautreau^a ; Michael Makowski^a ; Sylvie Perez^a ; Jana Polivkova^a ; Lucy Rogers^a ; Dennis O. Scott^b ; Andrew G. Swick^a ; Lucinda Thiede^a ; Catherine E. Trebino^a ; Richard V. Trilles^a ; Julie Wilmowski^a ; Yingxin Zhang^a
• 关键词：Cholecystokinin-1 receptor ; CCK1R ; Obesity ; Triazolobenzodiazepinone
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2943-2947
• 文件大小：655 K

摘要

New cholecystokinin-1 receptor (CCK1R) agonist 鈥榯riggers鈥?were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R鈥檚 located within the intestinal wall.