title: Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase.
abstract: alpha,gamma-Diketo acids (DKA) were discovered from screening as selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. The diketo acid moiety proved essential for activity, while substitution on the gamma position was necessary for selectivity and potency. Optimization led to the identification of a DKA inhibitor of NS5b polymerase with IC(50) = 45 nM, one of the most potent HCV NS5b polymerase inhibitors reported.
authors.affiliation: Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia, Rome, Italy. Vincenzo_summa@merck.com
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Licia
authors.initials: L
authors.lastname: Tomei
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Philippe
authors.initials: P
authors.lastname: Neuner
mesh_terms: D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000502:physiology*
chemical_list: D007651:Keto Acids; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase