Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors.
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.
Ontoria
Jesus M
JM
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
Rydberg
Edwin H
EH
Di Marco
Stefania
S
Tomei
Licia
L
Attenni
Barbara
B
Malancona
Savina
S
Martin Hernando
José I
JI
Gennari
Nadia
N
Koch
Uwe
U
Narjes
Frank
F
Rowley
Michael
M
Summa
Vincenzo
V
Carroll
Steve S
SS
Olsen
David B
DB
De Francesco
Raffaele
R
Altamura
Sergio
S
Migliaccio
Giovanni
G
Carfì
Andrea
A
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
D000998:Antiviral Agents; D007546:Isoquinolines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase