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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors.
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Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors.

机译：二醇基HIV蛋白酶抑制剂新型P2取代基的设计与合成。

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摘要

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.
机译：介绍了含有新型P2结构元件的HIV-1蛋白酶抑制剂的合成和SAR。设计抑制剂，其具有接受P2取代基的氢键，以利用抑制剂3作为模型模板探测与HIV-1蛋白酶骨架的ASP-29 / ASP-30的电位有利相互作用。通过从异丙基侧链或甲基酰胺部分附加氢键组合，通过从L-VAL甲基酰胺P2基序合成几种抑制剂。最有前景的抑制剂4a和4e分别显示了1.0nm和0.7nm的Ki值，并且在MT4细胞的基于MT4细胞的测定中分别为0.17微米和0.33μm的EC50值，与铅抑制剂3的效力略有损失。这些抑制剂也是如此针对携带M46i，V82F和I84V突变的HIV蛋白酶抑制剂抗性菌株进行测试。抑制剂4a和4e分别与HIV野生型相比显示3和4倍，而铅抑制剂3显示出较高的9倍变化。该研究进一步证明了各种P2取代基可以从内酯21中的一种化学步骤中引入各种P2取代基的方法的化学途径，使得能够体内地改性该抑制剂类中的整体性质。

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