Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, United States.
J Med Chem. 2011 Oct 27;54(20):7094-104. doi: 10.1021/jm201109t. Epub 2011 Sep 21.
Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.
由于目前尚无治愈 HIV 感染的方法，患者必须长期接受药物治疗，这引发了人们对潜在药物副作用和耐药性出现的担忧。出于这个原因，需要新的、安全的、对耐药 HIV 株具有更强效力的抗逆转录病毒药物。我们设计并合成了一系列对野生型（WT）病毒和耐药 HIV 株均具有很强活性的 HIV 蛋白酶抑制剂（PI）。在基于对称抑制剂系列的 P1 位置引入具有氢键供体和受体基团的取代基，可显著提高对耐药突变体的效力。通过这种方法，我们鉴定出了一些化合物，如 13、24 和 29，它们对来自先前 HIV PI 治疗失败的患者的高度突变 HIV 株的效力与化合物 1 相当或有所提高。总的来说，化合物 13 在抗耐药 HIV 株的效力和药代动力学研究中的口服生物利用度方面表现出了最佳的平衡。还报告了一种具有改善耐药谱的 HIV PI 与 WT HIV 蛋白酶结合的 X 射线分析结果。
