1208109-07-2Relevant articles and documents
5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors
Arasappan, Ashok,Bennett, Frank,Girijavallabhan, Vinay,Huang, Yuhua,Huelgas, Regina,Alvarez, Carmen,Chen, Lei,Gavalas, Stephen,Kim, Seong-Heon,Kosinski, Aneta,Pinto, Patrick,Rizvi, Razia,Rossman, Randall,Shankar, Bandarpalle,Tong, Ling,Velazquez, Francisco,Venkatraman, Srikanth,Verma, Vishal A.,Kozlowski, Joseph,Shih, Neng-Yang,Piwinski, John J.,MacCoss, Malcolm,Kwong, Cecil D.,Clark, Jeremy L.,Fowler, Anita T.,Geng, Feng,Kezar III, Hollis S.,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,Njoroge, F. George
scheme or table, p. 3229 - 3234 (2012/06/18)
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.
