Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

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• 作者：Arun K. Ghosh ; Heather L. Osswald ; Kristof Glauninger ; Johnson Agniswamy ; Yuan-Fang Wang ; Hironori Hayashi ; Manabu Aoki ; Irene T. Weber ; Hiroaki Mitsuya
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6826-6837
• 全文大小：620K
• 年卷期：0
• ISSN：1520-4804

文摘

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor–protein interaction.