title: Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.
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.
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Dousson
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: François-René
authors.initials: FR
authors.lastname: Alexandre
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Amador
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bonaric
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bot
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillet
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Convard
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: da Costa
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lioure
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Arlène
authors.initials: A
authors.lastname: Roland
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Rosinovsky
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maldonado
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Parsy
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Trochet
authors.affiliation: IDENIX, an MSD Company , 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Cedex 4 Montpellier, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Alistair
authors.initials: A
authors.lastname: Stewart
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Wang
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Mayes
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Chiara
authors.initials: C
authors.lastname: Musiu
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Poddesu
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Luana
authors.initials: L
authors.lastname: Vargiu
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Adel
authors.initials: A
authors.lastname: Moussa
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Jakubik
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Luke
authors.initials: L
authors.lastname: Hubbard
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.affiliation: IDENIX , 320 Bent Street, 4th Floor, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Standring
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010721:Phosphinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; C534138:IDX 899; D007211:Indoles; D010721:Phosphinic Acids; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase