Rapid Discovery and Structure-Activity Profiling of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Protease Enabled by the Copper(I)-Catalyzed Synthesis of 1,2,3-Triazoles and Their Further F

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• 作者：Matthew Whiting ; Jonathan C. Tripp ; Ying-Chuan Lin ; William Lindstrom ; Arthur J. Olson ; John H. Elder ; K. Barry Sharpless ; Valery V. Fokin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7697 - 7710
• 全文大小：376K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

Building from the results of a computational screen of a range of triazole-containing compounds for bindingefficiency to human immunodeficiency virus type 1 protease (HIV-1-Pr), a novel series of potent inhibitorshas been developed. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), which provides readyaccess to 1,4-disubstituted-1,2,3-triazoles, was used to unite a focused library of azide-containing fragmentswith a diverse array of functionalized alkyne-containing building blocks. In combination with direct screeningof the crude reaction products, this method led to the rapid identification of a lead structure and readilyenabled optimization of both azide and alkyne fragments. Replacement of the triazole with a range ofalternative linkers led to greatly reduced protease inhibition; however, further functionalization of the triazolesat the 5-position gave a series of compounds with increased activity, exhibiting K_i values as low as 8 nM.