title: Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.
abstract: Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
authors: Department of Chemistry Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA. rosmith@angio.com
authors: Roger A
authors: RA
authors: Smith
authors: Zahra
authors: Z
authors: Fathi
authors: Furahi
authors: F
authors: Achebe
authors: Christiana
authors: C
authors: Akuche
authors: Su-Ellen
authors: SE
authors: Brown
authors: Soongyu
authors: S
authors: Choi
authors: Jianmei
authors: J
authors: Fan
authors: Susan
authors: S
authors: Jenkins
authors: Harold C E
authors: HC
authors: Kluender
authors: Anish
authors: A
authors: Konkar
authors: Rico
authors: R
authors: Lavoie
authors: Ronald
authors: R
authors: Mays
authors: Jennifer
authors: J
authors: Natoli
authors: Stephen J
authors: SJ
authors: O'Connor
authors: Astrid A
authors: AA
authors: Ortiz
authors: Ning
authors: N
authors: Su
authors: Christy
authors: C
authors: Taing
authors: Susan
authors: S
authors: Tomlinson
authors: Theresa
authors: T
authors: Tritto
authors: Gan
authors: G
authors: Wang
authors: Stephan-Nicholas
authors: SN
authors: Wirtz
authors: Wai
authors: W
authors: Wong
authors: Xiao-Fan
authors: XF
authors: Yang
authors: Shihong
authors: S
authors: Ying
authors: Zhonghua
authors: Z
authors: Zhang
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D007093:Imidazoles; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; C029899:imidazole