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

详细信息    查看全文

• 作者：Cyril Dousson ; François-René Alexandre ; Agnès Amador ; Séverine Bonaric ; Stéphanie Bot ; Catherine Caillet ; Thierry Convard ; Daniel da Costa ; Marie-Pierre Lioure ; Arlène Roland ; Elodie Rosinovsky ; Sébastien Maldonado ; Christophe Parsy ; Christophe Trochet ; Richard Storer ; Alistair Stewart ; Jingyang Wang ; Benjamin A. Mayes ; Chiara Musiu ; Barbara Poddesu ; Luana Vargiu ; Michel Liuzzi ; Adel Moussa ; Jocelyn Jakubik ; Luke Hubbard ; Maria Seifer ; David Standring
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1891-1898
• 全文大小：448K
• ISSN：1520-4804

文摘

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 R_P-13s (IDX899) having an EC₅₀ of 11 nM against the Y181C/K103N double mutant.