Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors
| Autor: | Jeremy Clark, Xiao Tong, Ashok Arasappan, Randall R. Rossman, Anita T. Fowler, Subramaniam Ananthan, Vinay Girijavallabhan, Feng Geng, Regina Huelgas, Neng-Yang Shih, F. George Njoroge, Hollis S. Kezar, Joseph A. Maddry, Yuhua Huang, Frank Bennett, Cheng Li, John J. Piwinski, Cecil D. Kwong, John A. Secrist, Stephanie Curry, Abhijit Roychowdhury, Malcolm MacCoss, Robert C. Reynolds, Hsueh-Cheng Huang, Robert Chase |
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| Rok vydání: | 2012 |
| Předmět: |
Pyrimidine
Stereochemistry Clinical Biochemistry Pharmaceutical Science Hepacivirus Virus Replication Antiviral Agents Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pyridine Animals Moiety Replicon Enzyme Inhibitors Benzofuran Furans Molecular Biology Benzofurans Organic Chemistry Pyrimidine Nucleosides RNA-Dependent RNA Polymerase Rats Pyrimidines Liver chemistry Alkoxy group Molecular Medicine Selectivity Half-Life Methyl group |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:5144-5149 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2012.06.021 |
| Popis: | Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low. |
| Databáze: | OpenAIRE |
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