Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.
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.
Smith
Roger A
RA
Department of Chemistry Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA. rosmith@angio.com
Fathi
Zahra
Z
Achebe
Furahi
F
Akuche
Christiana
C
Brown
Su-Ellen
SE
Choi
Soongyu
S
Fan
Jianmei
J
Jenkins
Susan
S
Kluender
Harold C E
HC
Konkar
Anish
A
Lavoie
Rico
R
Mays
Ronald
R
Natoli
Jennifer
J
O'Connor
Stephen J
SJ
Ortiz
Astrid A
AA
Su
Ning
N
Taing
Christy
C
Tomlinson
Susan
S
Tritto
Theresa
T
Wang
Gan
G
Wirtz
Stephan-Nicholas
SN
Wong
Wai
W
Yang
Xiao-Fan
XF
Ying
Shihong
S
Zhang
Zhonghua
Z
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
D019440:Anti-Obesity Agents; D007093:Imidazoles; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; C029899:imidazole