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.
Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. robert.l.dow@pfizer.com
Robert L
RL
Dow
Philip A
PA
Carpino
John R
JR
Hadcock
Shawn C
SC
Black
Philip A
PA
Iredale
Paul
P
DaSilva-Jardine
Steven R
SR
Schneider
Ernest S
ES
Paight
David A
DA
Griffith
Dennis O
DO
Scott
Rebecca E
RE
O'Connor
Chudy I
CI
Nduaka
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