Synthesis and Biological Characterization of B-Ring Amino Analogues of Potent Benzothiadiazine Hepatitis C Virus Polymerase Inhibitors

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...

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Published in:Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3174-3183
Main Authors: Randolph, John T, Flentge, Charles A, Huang, Peggy P, Hutchinson, Douglas K, Klein, Larry L, Lim, Hock B, Mondal, Rubina, Reisch, Thomas, Montgomery, Debra A, Jiang, Wen W, Masse, Sherie V, Hernandez, Lisa E, Henry, Rodger F, Liu, Yaya, Koev, Gennadiy, Kati, Warren M, Stewart, Kent D, Beno, David W. A, Molla, Akhteruzzaman, Kempf, Dale J
Format: Article
Language:English
Subjects:
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacokinetics
Antiviral Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Benzothiadiazines - chemical synthesis
Benzothiadiazines - pharmacokinetics
Benzothiadiazines - pharmacology
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Genotype
Hepacivirus - enzymology
Hepacivirus - genetics
Liver - metabolism
Medical sciences
Microbial Sensitivity Tests
Pharmacology. Drug treatments
Rats
RNA Replicase - antagonists & inhibitors
Structure-Activity Relationship
Tissue Distribution
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Summary: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 EC50 values of 10 and 6 nM against genotypes 1a and 1b, respectively.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm801485z