对多药耐药病毒有效的HIV-1蛋白酶抑制剂的设计。

Design of HIV-1 protease inhibitors active on multidrug-resistant virus.

作者信息

Surleraux Dominique L N G, de Kock Herman A, Verschueren Wim G, Pille Geert M E, Maes Louis J R, Peeters Anik, Vendeville Sandrine, De Meyer Sandra, Azijn Hilde, Pauwels Rudi, de Bethune Marie-Pierre, King Nancy M, Prabu-Jeyabalan Moses, Schiffer Celia A, Wigerinck Piet B T P

机构信息

Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium.

出版信息

J Med Chem. 2005 Mar 24;48(6):1965-73. doi: 10.1021/jm049454n.

DOI:10.1021/jm049454n

PMID:15771440

Abstract

On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.

摘要

基于我们正在进行的HIV-1蛋白酶抑制剂项目中收集到的结构数据（我们的临床候选药物TMC114由此被选定），我们发现了新的稠合杂芳基磺酰胺系列。向P2'区域的进一步拓展旨在鉴定出具有改善的广谱活性和可接受药代动力学性质的新型化合物。这些化合物中有几种对一组高度交叉耐药的突变体显示出异常的广谱活性。这些系列中的某些成员在大鼠和犬中表现出良好的药代动力学特征。利用晶体结构和分子模拟来阐释因拓展至HIV-1蛋白酶的P2'口袋而产生的广谱特征。