Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein
| Autor: | Zhiping Xiong, Jeffrey J. Pouliot, Daniel J. Price, Andrew Maynard, Dulce Garrido, Andrew J. Peat, Katrina L. Creech, Todd M. Baughman, John W. Seal, Vincent W.-F. Tai, Luz Helena Kryn |
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| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
viruses Hepacivirus Clinical Biochemistry Pharmaceutical Science Viral Nonstructural Proteins Virus Replication Antiviral Agents Biochemistry chemistry.chemical_compound Drug Discovery Pyridine Humans Potency Spiro Compounds Molecular Targeted Therapy Replicon Molecular Biology EC50 biology Organic Chemistry biology.organism_classification In vitro Viral replication chemistry Drug Design Molecular Medicine Piperidine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 24:2288-2294 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.03.080 |
| Popis: | Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein. |
| Databáze: | OpenAIRE |
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