Optimization of 5-aryloxyimidazole non-nucleoside reverse transcriptase inhibitors
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Updated: Jun 29, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Lyn H Jones1, Gill Allan, Romuald Corbau
1Discovery Chemistry, Sandwich Laboratories, Pfizer Global Research and Development, Ramsgate Road, Kent, UK.
Abstract:
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their vulnerability to mutations in the allosteric binding site of reverse transcriptase that can result in the development of a resistant virus. Herein we present the optimization of a series of 5-aryloxy imidazoles, which possess a balanced pharmacological profile against both wild-type enzyme and the clinically relevant mutations K103N and Y181C. Subtle structural changes were used to probe structure-activity relationships relating to both potency and metabolic stability, which led to an imidazole derivative with an impressive overall profile.
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