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

  • Bioorg Med Chem Lett. 2012 Apr 15;22(8):2943-7. doi: 10.1016/j.bmcl.2012.02.049.
Kimberly O Cameron  1 ,  Elena E Beretta ,  Yue Chen ,  Margaret Chu-Moyer ,  Dilinie Fernando ,  Hua Gao ,  Jeffrey Kohrt ,  Sophie Lavergne ,  Paul Da Silva Jardine ,  Angel Guzman-Perez ,  Christopher Hoth ,  David A Perry ,  John R Hadcock ,  Denise Gautreau ,  Michael Makowski ,  Sylvie Perez ,  Jana Polivkova ,  Lucy Rogers ,  Dennis O Scott ,  Andrew G Swick ,  Lucinda Thiede ,  Catherine E Trebino ,  Richard V Trilles ,  Julie Wilmowski ,  Yingxin Zhang
Affiliations
  • 1. Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. [email protected]
PMID: 22424974 DOI: 10.1016/j.bmcl.2012.02.049
Abstract

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' 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's located within the intestinal wall.