Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor

J Med Chem. 2016 Mar 10;59(5):1891-8. doi: 10.1021/acs.jmedchem.5b01430.

Cyril Dousson ¹, François-René Alexandre ¹, Agnès Amador ¹, Séverine Bonaric ¹, Stéphanie Bot ¹, Catherine Caillet ¹, Thierry Convard ¹, Daniel da Costa ¹, Marie-Pierre Lioure ¹, Arlène Roland ¹, Elodie Rosinovsky ¹, Sébastien Maldonado ¹, Christophe Parsy ¹, Christophe Trochet ¹, Richard Storer ¹, Alistair Stewart ², Jingyang Wang ², Benjamin A Mayes ², Chiara Musiu ², Barbara Poddesu ², Luana Vargiu ², Michel Liuzzi ², Adel Moussa ², Jocelyn Jakubik ², Luke Hubbard ², Maria Seifer ², David Standring ²

Affiliations

1 IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
2 IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.

PMID: 26804933 DOI: 10.1021/acs.jmedchem.5b01430

Abstract

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.

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