Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists.
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| Abstract |
Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.
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| Authors | Shi-Liang Tseng, Ming-Shiu Hung, Chun-Ping Chang, Jen-Shin Song, Chia-Liang Tai, Hua-Hao Chiu, Wan-Ping Hsieh, Yinchiu Lin, Wan-Ling Chung, Chun-Wei Kuo, Chien-Huang Wu, Cheng-Ming Chu, Yen-Shih Tung, Yu-Sheng Chao, Kak-Shan Shia |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 17 Pg. 5397-412 (Sep 11 2008) ISSN: 1520-4804 [Electronic] United States |
| PMID | 18712856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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