Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold

✍ Scribed by 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; Michael D. Miller; Jay A. Grobler

• Book ID: 104004854
• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 320 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.08.135

✦ Synopsis

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).