Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
Eur J Med Chem. 2010 Jan;45(1):160-70. doi: 10.1016/j.ejmech.2009.09.038. Epub 2009 Oct 6.
The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 microM and 0.33 microM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.
本文介绍了含有新型 P2 结构单元的 HIV-1 蛋白酶抑制剂的合成和 SAR 研究。这些抑制剂的设计采用了氢键接受性的 P2 取代基，以探测与 HIV-1 蛋白酶骨架的 Asp-29/Asp-30 潜在有利的相互作用，利用抑制剂 3 作为模型模板。从 L-Val 甲基酰胺 P2 基序合成了几种抑制剂，通过在异丙基侧链或甲基酰胺部分附加氢键形成部分来进行。最有前途的抑制剂 4a 和 4e 的 Ki 值分别为 1.0 nM 和 0.7 nM，在 MT4 细胞测定中的 EC50 值分别为 0.17 μM 和 0.33 μM，与先导抑制剂 3 相比，效力略有下降。这些抑制剂还针对携带 M46I、V82F 和 I84V 突变的 HIV 蛋白酶抑制剂耐药株进行了测试。与 HIV 野生型相比，抑制剂 4a 和 4e 分别显示出 3 倍和 4 倍的变化，而先导抑制剂 3 则显示出更高的 9 倍变化。这项研究进一步证明了这种方法的化学可操作性，其中可以从内酯 21 仅通过一步化学转化引入各种 P2 取代基，从而能够轻松地改变此类抑制剂的整体特性。
