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 A
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：September 11, 2008
- 年：2008
- 卷：51
- 期：17
- 页码：5397-5412
- 全文大小：381K
- 年卷期：v.51,no.17(September 11, 2008)
- ISSN：1520-4804
文摘
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.