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Optimization of 5‐Aryloxyimidazole Non‐Nucleoside Reverse Transcriptase Inhibitors
Author(s) -
Jones Lyn H.,
Allan Gill,
Corbau Romuald,
Hay Duncan,
Middleton Donald S.,
Mowbray Charles E.,
Newman Sandra D.,
Perros Manos,
Randall Amy,
Vuong Hannah,
Webster Rob,
Westby Mike,
Williams David
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800183
Subject(s) - reverse transcriptase , nucleoside reverse transcriptase inhibitor , allosteric regulation , enzyme , nucleoside , human immunodeficiency virus (hiv) , chemistry , virology , biology , rna , stereochemistry , biochemistry , gene
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.