1. Synthesis and Biological Characterization of B-Ring Amino Analogues of Potent Benzothiadiazine Hepatitis C Virus Polymerase Inhibitors
- Author
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Rodger F. Henry, Gennadiy Koev, Larry L. Klein, David W A Beno, Debra Montgomery, John T. Randolph, Wen W. Jiang, Thomas Reisch, Charles A. Flentge, Warren M. Kati, Hutchinson Douglas K, Sherie Masse, Dale J. Kempf, Akhteruzzaman Molla, Kent D. Stewart, Lisa E. Hernandez, Peggy P. Huang, Yaya Liu, Hock Ben Lim, and Rubina Mondal
- Subjects
Genotype ,Hepatitis C virus ,Hepacivirus ,Microbial Sensitivity Tests ,Benzothiadiazines ,medicine.disease_cause ,Antiviral Agents ,Structure-Activity Relationship ,chemistry.chemical_compound ,Bacterial Proteins ,RNA polymerase ,Drug Discovery ,medicine ,Animals ,Tissue Distribution ,Replicon ,Enzyme Inhibitors ,NS5B ,Polymerase ,chemistry.chemical_classification ,biology ,RNA-Dependent RNA Polymerase ,Rats ,Enzyme ,Liver ,Biochemistry ,chemistry ,Benzothiadiazine ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - 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.
- Published
- 2009