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-pyra zole-3-carboxamide as a Novel Peripherally Restricted Cannabinoid-1 Receptor Antagonist with Significant Weight-Loss Efficacy in Diet-Induced Obese Mice

作者：Chang Chun Ping; Wu Chien Huang; Song Jen Shin; Chou Ming Chen; Wong Ying Chieh; Lin Yinchiu; Yeh Teng Kuang; Sadani Amit A; Ou Ming Hung; Chen Kun Hung; Chen Pei Hsuan; Kuo Po Chu; Tseng Chen Tso; Chang Kuei Hua; Tseng Shi Liang; Chao Yu Sheng; Hung Ming Shiu; Shia Kak Shan^*

来源：Journal of Medicinal Chemistry, 2013, 56(24): 9920-9933.

DOI：10.1021/jm401158e

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 angstrom(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.

• 出版日期2013-12-26