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

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• 作者：Chun-Ping Chang ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：9920-9933
• 全文大小：536K
• ISSN：1520-4804

文摘

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 脜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.