The Development of Cyclic Sulfolanes as Novel and High-Affinity P2 Ligands for HIV-1 Protease Inhibitors
作者:Arun K. Ghosh、Hee Yoon Lee、Wayne J. Thompson、Chris Culberson、M. Katharine Holloway、Sean P. McKee、Peter M. Munson、Tien T. Duong、Anthony M. Smith
DOI:10.1021/jm00034a016
日期:1994.4
synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore
描述并设计了一系列新的蛋白酶抑制剂,这些蛋白酶抑制剂结合了针对HIV-1蛋白酶S2底物结合位点的构象受限的环状配体。我们最近报道了3-四氢呋喃基的氨基甲酸酯作为HIV-1蛋白酶抑制剂的P2配体。随后,我们发现3(S)-羟基环丁砜的氨基甲酸酯进一步增加了这些抑制剂的体外效能。此外,在任一杂环系统的3-羟基上引入小的2-烷基顺式进一步增强了酶亲和力。迄今为止,顺-2-异丙基提供了最佳的抑制性能。这导致发现了抑制剂43(IC50 3.5 nM,与目前的临床候选药物1(Ro 31-8959)具有相似的体外抗病毒效力(CIC95 50 +/- 14 nM),但由于排除了P3喹啉配体,分子量降低。另外,已经证明八氢吡啶并衍生物34是P1'十氢异喹啉衍生物的有效替代物。