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