title: 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.
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.
authors.affiliation: Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Elliott
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.forename: Janice E
authors.initials: JE
authors.lastname: Chin
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Bartlett
authors.forename: Elena E
authors.initials: EE
authors.lastname: Beretta
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Paul Da Silva
authors.initials: Pda S
authors.lastname: Jardine
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Dubins
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Gillaspy
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Janet A
authors.initials: JA
authors.lastname: LaFlamme
authors.forename: Mary E
authors.initials: ME
authors.lastname: Lame
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Martin
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Nardone
authors.forename: Robert M
authors.initials: RM
authors.lastname: Oliver
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.forename: Dexue
authors.initials: D
authors.lastname: Sun
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Swick
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Trebino
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines