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Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors

  1. Author:
    Zhao, Xue Zhi
    Smith, Steven
    Maskell, Daniel P.
    Metifiot, Mathieu
    Pye, Valerie E.
    Fesen, Katherine
    Marchand, Christophe
    Pommier, Yves
    Cherepanov, Peter
    Hughes, Stephen
    Burke, Terrence

  2. Author Address

    NCI, Chem Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA.NCI, HIV Dynam & Replicat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA.NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NCI, Lab Mol Pharmacol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.Francis Crick Inst, Chromatin Struct & Mobile DNA, London NW1 1AT, England.Imperial Coll London, St Marys Campus,Norfolk Pl, London W2 1PG, England.
    1. Year: 2017
    2. Date: SEP 14
  2. Journal: Journal of Medicinal Chemistry
  3. AMER CHEMICAL SOC,
    1. 60
    2. 17
    3. Pages: 7315-7332
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    Integrase mutations can reduce the 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 analogues 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 analogues we have previously described.

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External Sources

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  2. DOI: 10.1021/acs.jmedchem.7b00596
  3. PMID: 28737946
  4. PMCID: PMC5601359
  5. View record in Web of Science®
  6. WOS: 000411171700008

Library Notes

  1. Fiscal Year: FY2016-2017
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