Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Ruebsam
Frank
F
Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc., 5871 Oberlin Drive, Suite 200, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
Murphy
Douglas E
DE
Tran
Chinh V
CV
Li
Lian-Sheng
LS
Zhao
Jingjing
J
Dragovich
Peter S
PS
McGuire
Helen M
HM
Xiang
Alan X
AX
Sun
Zhongxiang
Z
Ayida
Benjamin K
BK
Blazel
Julie K
JK
Kim
Sun Hee
SH
Zhou
Yuefen
Y
Han
Qing
Q
Kissinger
Charles R
CR
Webber
Stephen E
SE
Showalter
Richard E
RE
Shah
Amit M
AM
Tsan
Mei
M
Patel
Rupal A
RA
Thompson
Peggy A
PA
Lebrun
Laurie A
LA
Hou
Huiying J
HJ
Kamran
Ruhi
R
Sergeeva
Maria V
MV
Bartkowski
Darian M
DM
Nolan
Thomas G
TG
Norris
Daniel A
DA
Khandurina
Julia
J
Brooks
Jennifer
J
Okamoto
Ellen
E
Kirkovsky
Leo
L
D000998:Antiviral Agents / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase