Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors
Merck Research Laboratories, Kenilworth, NJ 07033, USA.Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 08/2012; 22(15):5144-9. DOI: 10.1016/j.bmcl.2012.06.021
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.
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ABSTRACT: The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.Bioorganic & medicinal chemistry letters 09/2012; 22(22):6967-73. DOI:10.1016/j.bmcl.2012.08.111 · 2.42 Impact Factor
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