title: 3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.
abstract: The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.
authors: Myrexis Inc., 305 Chipeta Way, Salt Lake City, UT 84108, USA.
authors: Dange V
authors: DV
authors: Kumar
authors: Roopa
authors: R
authors: Rai
authors: Ken A
authors: KA
authors: Brameld
authors: Jennifer
authors: J
authors: Riggs
authors: John R
authors: JR
authors: Somoza
authors: Ravi
authors: R
authors: Rajagopalan
authors: James W
authors: JW
authors: Janc
authors: Yu M
authors: YM
authors: Xia
authors: Tony L
authors: TL
authors: Ton
authors: Huiyong
authors: H
authors: Hu
authors: Isabelle
authors: I
authors: Lehoux
authors: Joseph D
authors: JD
authors: Ho
authors: Wendy B
authors: WB
authors: Young
authors: Barry
authors: B
authors: Hart
authors: Michael J
authors: MJ
authors: Green
mesh_terms: D000495:Allosteric Site; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology*; D006860:Hydrogen Bonding; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014965:X-Rays; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D015363:Quinolones; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase