title: 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.
abstract: 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.
authors.affiliation: Department of Cardiovascular, Metabolic, and Endocrine Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. david.a.griffith@pfizer.com
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Black
authors.forename: Philip A
authors.initials: PA
authors.lastname: Iredale
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
authors.forename: Paul
authors.initials: P
authors.lastname: DaSilva-Jardine
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Joseph
authors.initials: J
authors.lastname: DiBrino
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Landis
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: O'Connor
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
mesh_terms: 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
chemical_list: 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