Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

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• 作者：Xiongyu Wu ; Per 脰hrngren ; Advait A. Joshi ; Alejandro Trejos ; Magnus Persson ; Riina K. Arvela ; Hans Wallberg ; Lotta Vrang ; 脜sa Rosenquist ; Bertil B. Samuelsson ; Johan Unge ; Mats Larhed
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2724-2736
• 全文大小：788K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure 尾-hydroxy 纬-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K_i of 2.1 nM and an EC₅₀ of 0.64 渭M. Further optimization by decoration of the P1鈥?side chain furnished an even more potent HIV-1 protease inhibitor (K_i = 0.8 nM, EC₅₀ = 0.04 渭M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).