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Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold. 2010
Peter D Williams, and
Donnette D Staas, and
Shankar Venkatraman, and
H Marie Loughran, and
Rowena D Ruzek, and
Theresa M Booth, and
Terry A Lyle, and
John S Wai, and
Joseph P Vacca, and
Bradley P Feuston, and
Linda T Ecto, and
Jessica A Flynn, and
Daniel J DiStefano, and
Daria J Hazuda, and
Carolyn M Bahnck, and
Amy L Himmelberger, and
Geetha Dornadula, and
Renee C Hrin, and
Kara A Stillmock, and
Marc V Witmer, and
Michael D Miller, and
Jay A Grobler
Department of Medicinal Chemistry, Merck and Co., Inc., West Point, PA 19486, USA. peter_williams@merck.com
Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 μM, HIV RT RNase H; 13 μM, HIV RT-polymerase; 24 μM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 μM) with a modest window with respect to cytotoxicity (CC(50)=3.3 μM).
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