title: Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors.
abstract: Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. john.randolph@abbott.com
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.forename: Charles A
authors.initials: CA
authors.lastname: Flentge
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Huang
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Hutchinson
authors.forename: Larry L
authors.initials: LL
authors.lastname: Klein
authors.forename: Hock B
authors.initials: HB
authors.lastname: Lim
authors.forename: Rubina
authors.initials: R
authors.lastname: Mondal
authors.forename: Thomas
authors.initials: T
authors.lastname: Reisch
authors.forename: Debra A
authors.initials: DA
authors.lastname: Montgomery
authors.forename: Wen W
authors.initials: WW
authors.lastname: Jiang
authors.forename: Sherie V
authors.initials: SV
authors.lastname: Masse
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hernandez
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Yaya
authors.initials: Y
authors.lastname: Liu
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005838:Genotype; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000998:Antiviral Agents; D001426:Bacterial Proteins; D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D012324:RNA-Dependent RNA Polymerase