title: 2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis.
abstract: Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti S.p.A. (Merck Research Laboratories, Rome), Via Pontina Km 30,600, 00040 Pomezia, Italy. uwe_koch@merck.com
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Barbara
authors.initials: B
authors.lastname: Attenni
authors.forename: Savina
authors.initials: S
authors.lastname: Malancona
authors.forename: Stefania
authors.initials: S
authors.lastname: Colarusso
authors.forename: Immacolata
authors.initials: I
authors.lastname: Conte
authors.forename: Marcello
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Barbara
authors.initials: B
authors.lastname: Pacini
authors.forename: Claudia
authors.initials: C
authors.lastname: Giomini
authors.forename: Steven
authors.initials: S
authors.lastname: Thomas
authors.forename: Ilario
authors.initials: I
authors.lastname: Incitti
authors.forename: Licia
authors.initials: L
authors.lastname: Tomei
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry; D003460:Crystallization; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008782:Methylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002614:Chelating Agents; D008782:Methylurea Compounds; D011743:Pyrimidines; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C509708:2-(3-((((2-chlorobenzyl)amino)carbonyl)amino)-2-thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase