Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
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DOI：
10.1016/j.bmc.2006.05.063
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Kempf, Dale
中科院分区：
文献类型：
--
作者：
Flosi, William J.;DeGoey, David A.;Kempf, Dale
基于(R)-(羟乙基氨基)磺酰胺等排体与洛匹那韦环脲成分的组合，设计并合成了一系列新的HIV蛋白酶抑制剂。该系列通过用咪唑烷-2,4-二酮取代 6 元环脲接头进行优化，该咪唑烷-2,4-二酮很容易进行 N-烷基化，以掺入各种亚甲基连接的杂环基团，这些基团可以有利地结合在 HIV 蛋白酶的位点 3 上。与洛匹那韦相比，与野生型病毒 (pNL4-3) 和洛匹那韦耐药突变病毒 A17（由 HIV-1 (pNL4-3) 在 NIT-4 细胞中体外连续传代产生）相比，细胞培养活性显着改善。选择含有 Pi 的咪唑烷-2,4-二酮在抑制高耐药患者分离株 Pt1 和 Pt2 方面也比洛匹那韦更有效。当大鼠与等量利托那韦（各 5 mg/kg）共同口服给药时，该系列化合物收集的药代动力学数据变化很大。 AUC值范围为0.144至12.33μg·h/mL。 (c) 2006 Elsevier Ltd. 保留所有权利。
A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in NIT-4 cells). Select imidazolidine-2,4-dione containing Pis were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 mu g h/mL. (c) 2006 Elsevier Ltd. All rights reserved.