Identification and Biological Evaluation of a Series of 1H-Benzo[de]isoquinoline-1,3(2H)-diones as Hepatitis C Virus NS5B Polymerase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 52; no. 16; pp. 5217 - 5227
• Main Authors: Ontoria, Jesus M, Rydberg, Edwin H, Di Marco, Stefania, Tomei, Licia, Attenni, Barbara, Malancona, Savina, Martin Hernando, José I, Gennari, Nadia, Koch, Uwe, Narjes, Frank, Rowley, Michael, Summa, Vincenzo, Carroll, Steve S, Olsen, David B, De Francesco, Raffaele, Altamura, Sergio, Migliaccio, Giovanni, Carfì, Andrea
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.08.2009; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Chemistry, Medicinal; Crystallography, X-Ray; Drug Resistance, Viral; Genotype; Hepacivirus - genetics; Hepacivirus - physiology; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Mutation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Replicon - drug effects; Science & Technology; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Virus Replication; NONNUCLEOSIDE INHIBITORS; DEPENDENT RNA-POLYMERASE; MECHANISM; CRYSTAL-STRUCTURE; HCVNS5B POLYMERASE; RECENT PROGRESS; REPLICON VARIANTS; BINDING; ALLOSTERIC INHIBITORS; PROTEASE; Rat; Nitrogen heterocycle; Modeling; Imide; Structure activity relation; Molecular model; Antiviral; Bromine Organic compounds; Aromatic compound; Mechanism of action; Chemical synthesis; Ether; Enzyme; Transferases; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Bioavailability; Tricyclic compound; In vitro; RNA-directed RNA polymerase; Primary alcohol; Virus; In vivo; Nucleotidyltransferases; Vertebrata; Mammalia; Animal; Flaviviridae; Pharmacokinetics; Hepatitis C virus; Hepacivirus; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900517t

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 ΔC55-1b and ΔC21-2b 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.