UGA Center for Drug Discovery, the College of Pharmacy, R.C. Wilson Pharmacy Bldg., Room 320, University of Georgia, Athens, GA 30602, USA.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4112-6. doi: 10.1016/j.bmcl.2013.05.050. Epub 2013 May 23.
While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile.
虽然已经有一些整合酶抑制剂的例子表现出很强的抗 HIV 活性，但很少有报道称整合酶抑制剂在抗 HIV 活性方面存在显著差异，这些差异是由顺式和反式构型以及对映体立体结构的区别引起的。我们在这里描述了两种对映体反式羟基环戊基酰胺的设计和合成，它们在抗 HIV 活性方面表现出显著差异。这种差异可以通过它们在 HIV-1 整合酶内切体的活性部位的结合相互作用来解释。活性更高的对映异构体 3（EC50 为 25nM）在人肝微粒体中相对稳定。动力学数据显示，它对关键细胞色素 P450 同工酶的影响无论是作为抑制剂还是激活剂都很小，这表明它具有良好的 CYP 特征。
