Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors

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• 作者：Vinay M. Girijavallabhan ; Carmen Alvarez ; Frank Bennett ; Lei Chen ; Stephen Gavalas ; Yuhua Huang ; Seong-Heon Kim ; Aneta Kosinski ; Patrick Pinto ; Razia Rizvi ; R ; all Rossman ; B ; arpalle Shankar ; Ling Tong ; Francisco Velazquez ; Srikanth Venkatraman ; Vishal A. Verma ; Joseph Kozlowski ; Neng-Yang Shih ; John J. Piwinski ; Malcolm MacCoss ; et al.
• 关键词：HCV replication inhibitor ; HCV replicase inhibitor ; Carbanucleoside-like ; Pyridothiazole ; C&ndash ; H arylation ; 5-Aryl pyrimidine ; Pyridothiazole pyrimidine
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 September, 2012
• 年：2012
• 卷：22
• 期：17
• 页码：5652-5657
• 全文大小：2480 K

文摘

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R¹, R² or R³ positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC₅₀), PK parameters in all species studied, and cross genotype activity.