Discovery of 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced obese mice.
After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 (B/P = 1/33) with different electronegative groups. Especially when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Å(2), a threshold considered to possess a low probability to cross BBB, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound 4 also displays 163 clean off-target profiles and is currently under development for treating obesity and the related metabolic syndrome.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli County 35053, Taiwan, R.O.C.
Chun-Ping
CP
Chang
Chien-Huang
CH
Wu
Jen-Shin
JS
Song
Ming-Chen
MC
Chou
Ying-Chieh
YC
Wong
Yinchiu
Y
Lin
Teng-Kuang
TK
Yeh
Amit A
AA
Sadani
Ming-Hung
MH
Ou
Kun-Hung
KH
Chen
Pei-Hsuan
PH
Chen
Po-Chu
PC
Kuo
Chen-Tso
CT
Tseng
Kuei-Hua
KH
Chang
Shi-Liang
SL
Tseng
Yu-Sheng
YS
Chao
Ming-Shiu
MS
Hung
Kak-Shan
KS
Shia
D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015431:Weight Loss / Q000187:drug effects*
C586720:1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides