Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid.
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.
Stansfield
Ian
I
Department of Medicinal Chemistry, IRBM/MRL Rome, Via Pontina Km 30,600, Pomezia, 00040 Rome, Italy.
Avolio
Salvatore
S
Colarusso
Stefania
S
Gennari
Nadia
N
Narjes
Frank
F
Pacini
Barbara
B
Ponzi
Simona
S
Harper
Steven
S
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
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