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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801485z

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.