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

  • J Med Chem. 2013 Dec 27;56(24):9920-33. doi: 10.1021/jm401158e.
Chun-Ping Chang  1 ,  Chien-Huang Wu ,  Jen-Shin Song ,  Ming-Chen Chou ,  Ying-Chieh Wong ,  Yinchiu Lin ,  Teng-Kuang Yeh ,  Amit A Sadani ,  Ming-Hung Ou ,  Kun-Hung Chen ,  Pei-Hsuan Chen ,  Po-Chu Kuo ,  Chen-Tso Tseng ,  Kuei-Hua Chang ,  Shi-Liang Tseng ,  Yu-Sheng Chao ,  Ming-Shiu Hung ,  Kak-Shan Shia
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli County 35053, Taiwan, R.O.C.
PMID: 24224693 DOI: 10.1021/jm401158e
Abstract

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.

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