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Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2009 Nov 15; Vol. 19 (22), pp. 6404-12. Date of Electronic Publication: 2009 Sep 17. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Antiviral Agents pharmacokinetics
Chemistry, Pharmaceutical
Crystallography, X-Ray
Drug Evaluation, Preclinical
Genotype
Hepacivirus drug effects
Hepatitis C
Molecular Structure
RNA-Dependent RNA Polymerase
Viral Nonstructural Proteins antagonists & inhibitors
Biological Availability
Drug Design
Structure-Activity Relationship
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 19
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 19818610
- Full Text :
- https://doi.org/10.1016/j.bmcl.2009.09.045