Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice.
By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.
Wu
Chien-Huang
CH
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan, ROC.
Hung
Ming-Shiu
MS
Song
Jen-Shin
JS
Yeh
Teng-Kuang
TK
Chou
Ming-Chen
MC
Chu
Cheng-Ming
CM
Jan
Jiing-Jyh
JJ
Hsieh
Min-Tsang
MT
Tseng
Shi-Liang
SL
Chang
Chun-Ping
CP
Hsieh
Wan-Ping
WP
Lin
Yinchiu
Y
Yeh
Yen-Nan
YN
Chung
Wan-Ling
WL
Kuo
Chun-Wei
CW
Lin
Chin-Yu
CY
Shy
Horng-Shing
HS
Chao
Yu-Sheng
YS
Shia
Kak-Shan
KS
D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004032:Diet; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D004435:Eating / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D013379:Substrate Specificity; D013871:Thiones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use
C543043:2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazol-3-yl)-1,5,5-trimethyl-1,5-dihydroimidazol-4-thione; D019440:Anti-Obesity Agents; D007093:Imidazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013871:Thiones; C029899:imidazole