Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist.
We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.
Griffith
David A
DA
Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. david.a.griffith@pfizer.com
Hadcock
John R
JR
Black
Shawn C
SC
Iredale
Philip A
PA
Carpino
Philip A
PA
DaSilva-Jardine
Paul
P
Day
Robert
R
DiBrino
Joseph
J
Dow
Robert L
RL
Landis
Margaret S
MS
O'Connor
Rebecca E
RE
Scott
Dennis O
DO
D000818:Animals; D004285:Dogs; D055808:Drug Discovery; D004734:Energy Metabolism; D005223:Fats / Q000378:metabolism; D010084:Oxidation-Reduction; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C535235:1-(9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl)-4-ethylaminopiperidine-4-carboxylic acid amide; D005223:Fats; D010880:Piperidines; D011687:Purines; D043884:Receptor, Cannabinoid, CB1