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.

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“…In medical science, indole based therapeutic drugs possess valuable biologic activities such as anti-HIV (Human immunodeficiency virus), antimicrobial, anti-malarial, antiviral, anti-fungal, antileishmanial, anti-oxidant, and anti-tubercular Fig. 1B [26][27][28][29][30][31][32][33] . Indole is a principal structural molecule which is explained as a privileged scaffold.…”

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…Recently,A lexandre and co-workers reportedad etailed procedure of identifying aryl-phospho-indole (IDX899)a sahighly potent NNRTI against the most prevalent mutantstrains K103N and Y181C and the double-mutant strain RES056. [66] The structural modification of the lead compound 101 resulted in the following facts about SARs:M ost of the mono-substituted phenyl-phosphino indoles were highly active against the wildtype HIV-1 strain. To be active against mutants trains, long lipophilic substituents were neededt ob ei ncorporated into the structure.…”

Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors

“…In February 2009 it was licensed to GlaxoSmithKline and its name was changed to fosdevirine/GSK2248761. 76 In phase I clinical trials increased CD4+ cell counts in treatment-naïve patients infected with HIV-1 77 , 78 ( Chart 8 ).…”