title: Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064, USA. rolf.wagner@abbott.com
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Larson
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Todd D
authors.initials: TD
authors.lastname: Bosse
authors.forename: John F
authors.initials: JF
authors.lastname: Darbyshire
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gates
authors.forename: Wenping
authors.initials: W
authors.lastname: He
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hernandez
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: Wen W
authors.initials: WW
authors.lastname: Jiang
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Larry L
authors.initials: LL
authors.lastname: Klein
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.forename: William
authors.initials: W
authors.lastname: Kohlbrenner
authors.forename: A Chris
authors.initials: AC
authors.lastname: Krueger
authors.forename: Jinrong
authors.initials: J
authors.lastname: Liu
authors.forename: Yaya
authors.initials: Y
authors.lastname: Liu
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Long
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Sherie V
authors.initials: SV
authors.lastname: Masse
authors.forename: Tim
authors.initials: T
authors.lastname: Middleton
authors.forename: Debra A
authors.initials: DA
authors.lastname: Montgomery
authors.forename: John K
authors.initials: JK
authors.lastname: Pratt
authors.forename: Patricia
authors.initials: P
authors.lastname: Stuart
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
mesh_terms: 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
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D012321:DNA-Directed RNA Polymerases