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
| Autor: | Hua-Hao Chiu, Jen-Shin Song, Wan-Ping Hsieh, Ming-Shiu Hung, Cheng-Ming Chu, Kak-Shan Shia, Yen-Shih Tung, Chun-Ping Chang, Yu-Sheng Chao, Shi-Liang Tseng, Chien-Huang Wu, Yinchiu Lin, Wan-Ling Chung, Chia-Liang Tai, Chun-Wei Kuo |
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| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 51:5397-5412 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800066v |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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