title: 5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.
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.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. ashok.arasappan@merck.com
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Vinay
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.forename: Regina
authors.initials: R
authors.lastname: Huelgas
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Seong-Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Aneta
authors.initials: A
authors.lastname: Kosinski
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Razia
authors.initials: R
authors.lastname: Rizvi
authors.forename: Randall
authors.initials: R
authors.lastname: Rossman
authors.forename: Bandarpalle
authors.initials: B
authors.lastname: Shankar
authors.forename: Ling
authors.initials: L
authors.lastname: Tong
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Verma
authors.forename: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: John J
authors.initials: JJ
authors.lastname: Piwinski
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Cecil D
authors.initials: CD
authors.lastname: Kwong
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Clark
authors.forename: Anita T
authors.initials: AT
authors.lastname: Fowler
authors.forename: Feng
authors.initials: F
authors.lastname: Geng
authors.forename: Hollis S
authors.initials: HS
authors.lastname: Kezar
authors.forename: Abhijit
authors.initials: A
authors.lastname: Roychowdhury
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reynolds
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Maddry
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: John A
authors.initials: JA
authors.lastname: Secrist
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.forename: Stephanie
authors.initials: S
authors.lastname: Curry
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D008745:Methylation; D011743:Pyrimidines / Q000737:chemistry*; D012377:Rodentia; D013045:Species Specificity; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D052160:Benzothiazoles; D011743:Pyrimidines; C005465:benzothiazole