Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide,an orally active,gut-selective CCK1 receptor agonist for the potential treatment of obesity |
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| Authors: | Richard L Elliott Kimberly O Cameron Janice E Chin Jeremy A Bartlett Elena E Beretta Yue Chen Paul Da Silva Jardine Jeffrey S Dubins Melissa L Gillaspy Diane M Hargrove Amit S Kalgutkar Janet A LaFlamme Mary E Lame Kelly A Martin Tristan S Maurer Nancy A Nardone Robert M Oliver Dennis O Scott Dexue Sun Andrew G Swick Yingxin Zhang |
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| Institution: | 1. Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, United States;2. Department of Pharmaceutical Sciences, Pfizer Global Research and Development, Groton, CT 06340, United States;3. Department of Drug Metabolism and Disposition, Pfizer Global Research and Development, Groton, CT 06340, United States |
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| Abstract: | We describe the design, synthesis, and structure–activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents. |
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