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Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold |
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| Authors: | Peter D Williams Donnette D Staas Shankar Venkatraman H Marie Loughran Rowena D Ruzek Theresa M Booth Terry A Lyle John S Wai Joseph P Vacca Bradley P Feuston Linda T Ecto Jessica A Flynn Daniel J DiStefano Daria J Hazuda Carolyn M Bahnck Amy L Himmelberger Geetha Dornadula Renee C Hrin Kara A Stillmock Marc V Witmer Jay A Grobler |
| Institution: | 1. Department of Medicinal Chemistry, Merck and Co., Inc., West Point, PA 19486, USA;2. Department of Chemistry Modeling and Informatics, Merck and Co., Inc., West Point, PA 19486, USA;3. Department of Vaccine Basic Research, Merck and Co., Inc., West Point, PA 19486, USA;4. Department of Research Medicine Administration, Merck and Co., Inc., West Point, PA 19486, USA;5. Department of Antiviral Research, Merck and Co., Inc., West Point, PA 19486, USA |
| Abstract: | 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 (IC50 = 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 (IC50 = 0.19 μM) with a modest window with respect to cytotoxicity (CC50 = 3.3 μM). |
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