Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.
The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
Wagner
Rolf
R
Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064, USA. rolf.wagner@abbott.com
Larson
Daniel P
DP
Beno
David W A
DW
Bosse
Todd D
TD
Darbyshire
John F
JF
Gao
Yi
Y
Gates
Bradley D
BD
He
Wenping
W
Henry
Rodger F
RF
Hernandez
Lisa E
LE
Hutchinson
Douglas K
DK
Jiang
Wen W
WW
Kati
Warren M
WM
Klein
Larry L
LL
Koev
Gennadiy
G
Kohlbrenner
William
W
Krueger
A Chris
AC
Liu
Jinrong
J
Liu
Yaya
Y
Long
Michelle A
MA
Maring
Clarence J
CJ
Masse
Sherie V
SV
Middleton
Tim
T
Montgomery
Debra A
DA
Pratt
John K
JK
Stuart
Patricia
P
Molla
Akhteruzzaman
A
Kempf
Dale J
DJ
D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D012321:DNA-Directed RNA Polymerases