A minimally cytotoxic CD4 mimic as an HIV entry inhibitor
A minimally cytotoxic CD4 mimic as an HIV entry inhibitor
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DOI：
10.1016/j.bmcl.2015.11.103
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发表时间：
2016-01-15
影响因子：
2.7
通讯作者：
Tamamura, Hirokazu
中科院分区：
文献类型：
--
作者：
Mizuguchi, Takaaki;Harada, Shigeyoshi;Tamamura, Hirokazu
已经报道了几种CD 4模拟物作为HIV-1进入抑制剂，其可以阻断病毒包膜糖蛋白gp 120和细胞表面蛋白CD 4之间的相互作用。我们以前发现了一个具有高抗HIV活性和低细胞毒性的先导化合物2（YYA-021）。然而，药代动力学分析显示化合物2在大鼠和恒河猴中具有广泛的组织分布和相对高的分布体积。在本研究中，我们寻找更具亲水性的CD 4模拟物，以减少组织分布。发现一个新的化合物（5）具有较高的抗HIV活性，但没有明显的细胞毒性。化合物5比化合物2更亲水，并且在恒河猴中静脉内施用化合物5的药代动力学显示化合物5具有比化合物2更低的组织分布，表明化合物5具有更好的分布。(C)2015爱思唯尔有限公司版权所有。
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. (C) 2015 Elsevier Ltd. All rights reserved.