Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity.
We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.
Dow
Robert L
RL
Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. robert.l.dow@pfizer.com
Carpino
Philip A
PA
Hadcock
John R
JR
Black
Shawn C
SC
Iredale
Philip A
PA
DaSilva-Jardine
Paul
P
Schneider
Steven R
SR
Paight
Ernest S
ES
Griffith
David A
DA
Scott
Dennis O
DO
O'Connor
Rebecca E
RE
Nduaka
Chudy I
CI
D000818:Animals; D002986:Clinical Trials as Topic; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy*; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*
C540941:2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo(3,4-f)(1,4)oxazepin-8(5H)-one; D007769:Lactams; D010077:Oxazepines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1