title: Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold.
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 (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).
authors.affiliation: Department of Medicinal Chemistry, Merck and Co., Inc., West Point, PA 19486, USA. peter_williams@merck.com
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.forename: Donnette D
authors.initials: DD
authors.lastname: Staas
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: H Marie
authors.initials: HM
authors.lastname: Loughran
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Ruzek
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Booth
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: John S
authors.initials: JS
authors.lastname: Wai
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Feuston
authors.forename: Linda T
authors.initials: LT
authors.lastname: Ecto
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Flynn
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DiStefano
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Bahnck
authors.forename: Amy L
authors.initials: AL
authors.lastname: Himmelberger
authors.forename: Geetha
authors.initials: G
authors.lastname: Dornadula
authors.forename: Renee C
authors.initials: RC
authors.lastname: Hrin
authors.forename: Kara A
authors.initials: KA
authors.lastname: Stillmock
authors.forename: Marc V
authors.initials: MV
authors.lastname: Witmer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Jay A
authors.initials: JA
authors.lastname: Grobler
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*
chemical_list: C556786:1-hydroxy-1,8-naphthyridin-2(1H)-one; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D016914:Ribonuclease H