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J Med Chem. 2012 Dec 13;55(23):10601-9. doi: 10.1021/jm301294g. Epub 2012 Nov 26.

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

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  • 1GlaxoSmithKline Research & Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.


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.

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