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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Stanton, Richard A.¹  Lu, Xiao¹  Detorio, Mervi¹  Montero, Catherine¹  Hammond, Emily T.¹  Ehteshami, Maryam¹  Domaoal, Robert A.¹  Nettles, James H.¹  Feraud, Michel²  Schinazi, Raymond F.¹ 

[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

关键词: HIV;    Reverse transcriptase;    NNRTI;    FEP;   

DOI  :  10.1016/j.bmcl.2016.06.065

来源: Elsevier

【 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.

【 授权许可】

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