Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

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Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5144-9

Authors: Bennett F, Kezar HS, Girijavallabhan V, Huang Y, Huelgas R, Rossman R, Shih NY, Piwinski JJ, MacCoss M, Kwong CD, Clark JL, Fowler AT, Geng F, Roychowdhury A, Reynolds RC, Maddry JA, Ananthan S, Secrist JA, Li C, Chase R, Curry S, Huang HC, Tong X, George Njoroge F, Arasappan A

Abstract
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.

PMID: 22814211 [PubMed - in process]

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