title: Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors.
abstract: The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti, S.p.A. (IRBM-MRL Rome), Via Pontina Km 30,600, I-00040 Pomezia, Italy. jesus_ontoria@merck.com
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Ontoria
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Rydberg
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Marco
authors.forename: Licia
authors.initials: L
authors.lastname: Tomei
authors.forename: Barbara
authors.initials: B
authors.lastname: Attenni
authors.forename: Savina
authors.initials: S
authors.lastname: Malancona
authors.forename: José I
authors.initials: JI
authors.lastname: Martin Hernando
authors.forename: Nadia
authors.initials: N
authors.lastname: Gennari
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Steve S
authors.initials: SS
authors.lastname: Carroll
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfì
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D051381:Rats; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase