Imidazopyridazine Hepatitis C Virus Polymerase Inhibitors. Structure–Activity Relationship Studies and the Discovery of a Novel, Traceless Prodrug Mechanism
| Autor: | Amanda Mathis, Wenyan Mo, Susan Long, Stephanie Anna Chan, Jill Walker, Ryan Lauchli, Martin Robert Leivers, Elizabeth M. Turner, Tony Ton, Sebastian Liehr, J. Greg Falls, John F. Miller, Michael Youngman |
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| Rok vydání: | 2013 |
| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry Decarboxylation Hepatitis C virus hERG Hepacivirus Viral Nonstructural Proteins medicine.disease_cause Antiviral Agents Mass Spectrometry Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery medicine Animals Structure–activity relationship Potency Enzyme Inhibitors NS5B Polymerase biology Prodrug Rats Pyridazines chemistry biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 57:1964-1975 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented. |
| Databáze: | OpenAIRE |
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