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

Autor:	Elodie Rosinovsky, Catherine Caillet, Chiara Musiu, Jingyang Wang, Marie-Pierre Lioure, Arlène Roland, Luana Vargiu, Jocelyn Jakubik, Alistair Stewart, Michel Liuzzi, Richard Storer, Stéphanie Bot, Daniel Da Costa, Sébastien Maldonado, Barbara Poddesu, David Standring, Christophe Claude Parsy, Cyril B. Dousson, Christophe Trochet, Séverine Bonaric, Francois-Rene Alexandre, Maria Seifer, Adel Moussa, Benjamin Alexander Mayes, Agnès Amador, Luke Hubbard, Thierry Convard
Rok vydání:	2016
Předmět:	Male Models Molecular 0301 basic medicine Indoles Anti-HIV Agents Mutant Drug resistance Pharmacology Crystallography X-Ray 01 natural sciences Virus Cell Line Nucleoside Reverse Transcriptase Inhibitor Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences Dogs Drug Discovery Animals Humans Structure–activity relationship Indole test Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Drug discovery Chemistry virus diseases biochemical phenomena metabolism and nutrition Phosphinic Acids Virology HIV Reverse Transcriptase Reverse transcriptase Rats 0104 chemical sciences Macaca fascicularis 030104 developmental biology HIV-1 Hepatocytes Reverse Transcriptase Inhibitors Molecular Medicine
Zdroj:	Journal of Medicinal Chemistry. 59:1891-1898
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::176c9163cb45c8243cc2fc43da5fe84d https://doi.org/10.1021/acs.jmedchem.5b01430 Zobrazit plný text záznamu