Nugent R A, Schlachter S T, Murphy M J, Cleek G J, Poel T J, Wishka D G, Graber D R, Yagi Y, Keiser B J, Olmsted R A, Kopta L A, Swaney S M, Poppe S M, Morris J, Tarpley W G, Thomas R C
Departments of Medicinal Chemistry, Discovery Technology, and Infectious Diseases, Pharmacia & Upjohn, Kalamazoo, Michigan 49001-0199, USA.
J Med Chem. 1998 Sep 24;41(20):3793-803. doi: 10.1021/jm9800806.
A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.
合成了一系列嘧啶硫醚，并对其针对野生型HIV-1逆转录酶（RT）和携带赋予抗性突变P236L的RT的抑制特性进行了评估。嘧啶和通过硫醚连接的官能团的修饰产生了几种类似物，这些类似物对两种酶类型均表现出活性，对野生型的IC50值低至190 nM，对P236L RT的IC50值为66 nM。在细胞培养中对选定数量的嘧啶硫醚进行评估表明，这些化合物对HIV-1IIIB-WT具有优异的活性，并且对实验室衍生的HIV-1MF地拉韦啶抗性变体保持良好的活性。
