Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10592510 | Bioorganic & Medicinal Chemistry Letters | 2012 | 6 Pages |
Abstract
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Ashok Arasappan, Frank Bennett, Vinay Girijavallabhan, Yuhua Huang, Regina Huelgas, Carmen Alvarez, Lei Chen, Stephen Gavalas, Seong-Heon Kim, Aneta Kosinski, Patrick Pinto, Razia Rizvi, Randall Rossman, Bandarpalle Shankar, Ling Tong,