Global Research and Development, Pfizer Inc., San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2010 Dec 15;20(24):7429-34. doi: 10.1016/j.bmcl.2010.10.022. Epub 2010 Oct 13.
HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the β-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.
HIV-1 整合酶是 HIV 基因组编码的三种酶之一，对病毒复制至关重要，HIV-1 整合酶抑制剂已成为一种新的有前途的治疗药物。最近，我们报道了发现了具有强效抑制 HIV-1 整合酶作用的氮杂吲哚羟肟酸。N-甲基羟肟酸对氧化代谢稳定，但通过 2 相葡萄糖醛酸化途径迅速清除。我们能够在氮杂吲哚核心的β位引入极性基团，从而通过降低计算的 log D 值（c Log D）来改变物理性质，这导致人肝细胞中的清除率降低。代表性化合物在狗体内的药代动力学数据表明具有中等的口服生物利用度和合理的半衰期。在不对酶和抗病毒活性产生较大负面影响的情况下实现了这些目标，因此表明在未来的系列研究中有机会改变清除参数。
