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

• Type of Material: Article
• Authors: Richard A. Stanton, Emory University; Xiao Lu, Emory University; Mervi Detorio, Emory University; Catherine Montero, Emory University; Emily T. Hammond, Emory University; Maryam Ehteshami, Emory University; Robert Domaoal, Emory University; James Nettles, Emory University; Michel Feraud, PROVEPHARM; Raymond Schinazi, Emory University
• Language: English
• Date: 2016-08-15
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2016
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2016.06.065
• Title of Journal or Parent Work: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• Volume: 26
• Issue: 16
• Start Page: 4101
• End Page: 4105
• Grant/Funding Information: This work was facilitated in part by the NIH grant P30AI050409.
• Keywords: Chemistry; FEP; RESISTANCE; Reverse transcriptase; Pharmacology & Pharmacy; DOCKING; Chemistry, Organic; MET KINASE; ACCURACY; Physical Sciences; Chemistry, Medicinal; HIV; Science & Technology; NNRTI; DYNAMICS; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pharmacology; Chemistry, General; Health Sciences, Pharmacy

Abstract

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 μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50 = 9.2, 3.5 μM) 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 μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.