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Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors

DOI: 10.1021/acs.jmedchem.7b00596 DOI Help

Authors: Xue Zhi Zhao (National Cancer Institute, National Institutes of Health) , Steven J Smith (National Cancer Institute, National Institutes of Health) , Daniel P. Maskell (The Francis Crick Institute) , Mathieu Métifiot (National Cancer Institute, National Institutes of) , Valerie E. Pye (The Francis Crick Institute) , Katherine Fesen (National Cancer Institute, National Institutes of Health) , Christophe Marchand (National Cancer Institute, National Institutes of Health) , Yves Pommier (National Cancer Institute, National Institutes of Health) , Peter Cherepanov (Imperial College London; The Francis Crick Institute) , Stephen H Hughes (National Cancer Institute, National Institutes of Health) , Terrence R Burke (National Cancer Institute, National Institutes of Health)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2017
Diamond Proposal Number(s): 9424 , 13775

Abstract: Integrase mutations can reduce effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG) has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogs of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogs we have previously described.

Subject Areas: Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 26/07/2017 15:38

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acs.jmedchemn.pdf

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