A minimally cytotoxic CD4 mimic as an HIV entry inhibitor

作者：Mizuguchi Takaaki; Harada Shigeyoshi; Miura Tomoyuki; Ohashi Nami; Narumi Tetsuo; Mori Hiromi; Irahara Yu; Yamada Yuko; Nomura Wataru; Matsushita Shuzo; Yoshimura Kazuhisa^*; Tamamura Hirokazu

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(2): 397-400.

DOI：10.1016/j.bmcl.2015.11.103

• CD4 mimic
• Conformational change in gp120
• HIV entry inhibitor
• Pharmacokinetics

Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.

• 出版日期2016-1-15