Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors

被引：15

作者：

Stanton, Richard A. ^{[1
]}

Lu, Xiao ^{[1
]}

Detorio, Mervi ^{[1
]}

Montero, Catherine ^{[1
]}

Hammond, Emily T. ^{[1
]}

Ehteshami, Maryam ^{[1
]}

Domaoal, Robert A. ^{[1
]}

Nettles, James H. ^{[1
]}

Feraud, Michel ^{[2
]}

Schinazi, Raymond F. ^{[1
]}

机构：

[1] Emory Univ, Sch Med, Dept Pediat, Ctr AIDS Res,Lab Biochem Pharmacol, Atlanta, GA 30322 USA

[2] PROVEPHARM, 22 Rue Marc Donadille, F-13013 Marseille, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 16期

关键词：

HIV; Reverse transcriptase; NNRTI; FEP; MET KINASE; RESISTANCE; DOCKING; ACCURACY; DYNAMICS;

D O I：

10.1016/j.bmcl.2016.06.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index > 100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50 = 0.73 mu M) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50 = 9.2, 3.5 mu M) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50 = 0.36 mu M). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4101 / 4105

页数：5

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