Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease
| Autor: | Yoshiyuki Taoda, Toshiyuki Akiyama, Tomokazu Yoshinaga, Masayoshi Miyagawa, Kenji Tomita, Kenji Takaya, Kazunari Hattori, Shinya Shano, Takao Shishido, Akihiko Sato, Kazuya Yasuo, Makoto Kawai, Ryu Yoshida, Chika Takahashi-Kageyama |
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| Rok vydání: | 2019 |
| Předmět: |
Pyridones
Stereochemistry Substituent Microbial Sensitivity Tests Plasma protein binding Antiviral Agents 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Endonuclease Drug Discovery Structure–activity relationship Enzyme Inhibitors 030304 developmental biology EC50 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology Chemistry Cellular Assay fungi food and beverages Bridged Bicyclo Compounds Heterocyclic Endonucleases Orthomyxoviridae In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Docking (molecular) biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 62:8101-8114 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses. |
| Databáze: | OpenAIRE |
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