title: High potency improvements to weak aryl uracil HCV polymerase inhibitor leads.
abstract: Described herein is the development of a potent non-nucleoside, small molecule inhibitor of genotype 1 HCV NS5B Polymerase. A 23 μM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by additional manipulation of the R and R1 substituents. Subsequent modifications to improve physical properties were made in an attempt to achieve an acceptable pharmacokinetic profile.
authors.affiliation: AbbVie, Department R4AJ, Building AP52N, 1 North Waukegan Road, North Chicago, IL 60064, United States. pamela.l.donner@abbvie.com
authors.forename: Pamela
authors.initials: P
authors.lastname: Donner
authors.forename: John T
authors.initials: JT
authors.lastname: Randolph
authors.forename: Peggy
authors.initials: P
authors.lastname: Huang
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Clarence
authors.initials: C
authors.lastname: Maring
authors.forename: Ben Hock
authors.initials: BH
authors.lastname: Lim
authors.forename: Lynn
authors.initials: L
authors.lastname: Colletti
authors.forename: Yaya
authors.initials: Y
authors.lastname: Liu
authors.forename: Rubina
authors.initials: R
authors.lastname: Mondal
authors.forename: Jill
authors.initials: J
authors.lastname: Beyer
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: David
authors.initials: D
authors.lastname: Beno
authors.forename: Kenton
authors.initials: K
authors.lastname: Longenecker
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.forename: Akhter
authors.initials: A
authors.lastname: Molla
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000502:physiology; D051381:Rats; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D014498:Uracil; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase