Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2009-08, Vol.52 (16), p.5217-5227

Ort / Verlag

Columbus, OH: American Chemical Society

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.