Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

  • J Med Chem. 2012 Dec 13;55(23):10601-9. doi: 10.1021/jm301294g.
Pek Chong  1 ,  Paul Sebahar ,  Michael Youngman ,  Dulce Garrido ,  Huichang Zhang ,  Eugene L Stewart ,  Robert T Nolte ,  Liping Wang ,  Robert G Ferris ,  Mark Edelstein ,  Kurt Weaver ,  Amanda Mathis ,  Andrew Peat
Affiliations
  • 1. GlaxoSmithKline Research & Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
PMID: 23137340 DOI: 10.1021/jm301294g
Abstract

A new series of non-nucleoside Reverse Transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent Antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to Reverse Transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable Antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.