title: Synthesis and SAR of geminal substitutions at the C5' carbosugar position of pyrimidine-derived HCV inhibitors.
abstract: The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. verma.vishal@gene.com
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Verma
authors.forename: Randall
authors.initials: R
authors.lastname: Rossman
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavalas
authors.forename: Vinay
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
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: 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: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Cecil D
authors.initials: CD
authors.lastname: Kwong
authors.forename: Namita
authors.initials: N
authors.lastname: Bansal
authors.forename: Hollis S
authors.initials: HS
authors.lastname: Kezar
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
authors.forename: Ashok
authors.initials: A
authors.lastname: Arasappan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002241:Carbohydrates / Q000737:chemistry*; D004285:Dogs; D006207:Half-Life; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D002241:Carbohydrates; D011743:Pyrimidines; C030986:pyrimidine