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.