| Literature DB >> 22472692 |
Ashok Arasappan1, 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, Francisco Velazquez, Srikanth Venkatraman, Vishal A Verma, Joseph Kozlowski, Neng-Yang Shih, John J Piwinski, Malcolm MacCoss, Cecil D Kwong, Jeremy L Clark, Anita T Fowler, Feng Geng, Hollis S Kezar, Abhijit Roychowdhury, Robert C Reynolds, Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge.
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.Entities:
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Year: 2012 PMID： 22472692 DOI： 10.1016/j.bmcl.2012.03.036
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823