title: Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid.
abstract: 5,6-Dihydroxypyrimidine-4-carboxylic acids are a promising series of hepatitis C virus (HCV) NS5B polymerase inhibitors that bind at the active site of the enzyme. Here we report a simple 2-thienyl substituted analogue that shows 10-fold improved activity over the original lead, and which allowed us to further delineate the key elements of the pharmacophore of this class of inhibitor. This work led to the identification of a trifluoromethyl acylsulfonamide group as a viable replacement for the C4 carboxylic acid in this series.
authors.affiliation: Department of Medicinal Chemistry, IRBM/MRL Rome, Via Pontina Km 30,600, Pomezia, 00040 Rome, Italy.
authors.forename: Ian
authors.initials: I
authors.lastname: Stansfield
authors.forename: Salvatore
authors.initials: S
authors.lastname: Avolio
authors.forename: Stefania
authors.initials: S
authors.lastname: Colarusso
authors.forename: Nadia
authors.initials: N
authors.lastname: Gennari
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
authors.forename: Barbara
authors.initials: B
authors.lastname: Pacini
authors.forename: Simona
authors.initials: S
authors.lastname: Ponzi
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D016174:Hepacivirus; D006868:Hydrolysis; D011687:Purines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C498370:2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid; D000998:Antiviral Agents; D011687:Purines; D011725:Pyridines; D011743:Pyrimidines; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase