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.
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.
Elliott
Richard L
RL
Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, United States.
Cameron
Kimberly O
KO
Chin
Janice E
JE
Bartlett
Jeremy A
JA
Beretta
Elena E
EE
Chen
Yue
Y
Jardine
Paul Da Silva
Pda S
Dubins
Jeffrey S
JS
Gillaspy
Melissa L
ML
Hargrove
Diane M
DM
Kalgutkar
Amit S
AS
LaFlamme
Janet A
JA
Lame
Mary E
ME
Martin
Kelly A
KA
Maurer
Tristan S
TS
Nardone
Nancy A
NA
Oliver
Robert M
RM
Scott
Dennis O
DO
Sun
Dexue
D
Swick
Andrew G
AG
Trebino
Catherine E
CE
Zhang
Yingxin
Y
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
D019440:Anti-Obesity Agents; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines