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Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Oct 15; Vol. 18 (20), pp. 5635-9. Date of Electronic Publication: 2008 Aug 29. - Publication Year :
- 2008
-
Abstract
- The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
- Subjects :
- Antiviral Agents pharmacology
Caco-2 Cells
Crystallography, X-Ray methods
Cyclic S-Oxides pharmacology
DNA-Directed RNA Polymerases chemistry
Drug Design
Genotype
Humans
Inhibitory Concentration 50
Microsomes metabolism
Models, Chemical
Molecular Conformation
Pyridazines pharmacology
Structure-Activity Relationship
Thiadiazines pharmacology
Antiviral Agents chemical synthesis
Chemistry, Pharmaceutical methods
Cyclic S-Oxides chemical synthesis
Pyridazines chemical synthesis
Pyridazines chemistry
Thiadiazines chemical synthesis
Viral Nonstructural Proteins antagonists & inhibitors
Viral Nonstructural Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 18
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 18796353
- Full Text :
- https://doi.org/10.1016/j.bmcl.2008.08.094