Design and Synthesis of P1鈥揚3 Macrocyclic Tertiary-Alcohol-Comprising HIV-1 Protease Inhibitors

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• 作者：Advait Joshi ; Jean-Baptiste V茅ron ; Johan Unge ; 脜sa Rosenquist ; Hans Wallberg ; Bertil Samuelsson ; Anders Hallberg ; Mats Larhed
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：8999-9007
• 全文大小：517K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

To study P1鈥揚3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with K_i and EC₅₀ values down to 3.1 nM and 0.37 渭M, respectively.