Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

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• 作者：Frank Bennett ; Hollis S. Kezar III ; Vinay Girijavallabhan ; Yuhua Huang ; Regina Huelgas ; R ; all Rossman ; Neng-Yang Shih ; John J. Piwinski ; Malcolm MacCoss ; Cecil D. Kwong ; Jeremy L. Clark ; Anita T. Fowler ; Feng Geng ; Abhijit Roychowdhury ; Robert C. Reynolds ; Joseph A. Maddry ; Subramaniam Ananthan ; John A. Secrist III ; Cheng Li ; Robert Chase ; et al.
• 关键词：HCV replication inhibitor ; HCV replicase inhibitor ; Carbanucleoside-like ; 5-Aryl pyrimidine ; 5-Pyridofuranyl pyrimidine ; Hepatitis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：22
• 期：15
• 页码：5144-5149
• 全文大小：2576 K

文摘

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.