2. Academic Validation
  3. 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

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

Affiliation

  • 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.

Figures
Products