title: Novel substituted pyrimidines as HCV replication (replicase) inhibitors.
abstract: Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).
authors.affiliation: Southern Research Institute, Birmingham, AL 35205, USA. kwong@southernresearch.org
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: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.forename: John J
authors.initials: JJ
authors.lastname: Piwinski
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Boris
authors.initials: B
authors.lastname: Feld
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: F
authors.initials: F
authors.lastname: George Njoroge
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D011743:Pyrimidines