Bioorganic and Medicinal Chemistry Letters p. 5144 - 5149 (2012)
Update date:2022-09-26
Topics:
Bennett, Frank
Kezar III, Hollis S.
Girijavallabhan, Vinay
Huang, Yuhua
Huelgas, Regina
Rossman, Randall
Shih, Neng-Yang
Piwinski, John J.
MacCoss, Malcolm
Kwong, Cecil D.
Clark, Jeremy L.
Fowler, Anita T.
Geng, Feng
Roychowdhury, Abhijit
Reynolds, Robert C.
Maddry, Joseph A.
Ananthan, Subramaniam
Secrist III, John A.
Li, Cheng
Chase, Robert
Curry, Stephanie
Huang, Hsueh-Cheng
Tong, Xiao
George Njoroge
Arasappan, Ashok
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 CC50) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC50) was low.
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