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.
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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Cell Line
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Crystallography, X-Ray
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Dogs
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Dose-Response Relationship, Drug
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Drug Discovery*
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects*
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HIV-1 / enzymology*
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Hepatocytes / chemistry
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Hepatocytes / metabolism
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Macaca fascicularis
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Male
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Models, Molecular
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Molecular Structure
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Phosphinic Acids / chemical synthesis
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Phosphinic Acids / chemistry
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Phosphinic Acids / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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IDX 899
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Indoles
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Phosphinic Acids
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase