Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators
| Autor: | Yazen Alnouti, Corey R. Hopkins, Kristopher K. Abney, Nagsen Gautam, Krystian A. Kozek, Sushil Kumar, Swagat Sharma, C. David Weaver |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Potassium Clinical Biochemistry Tetrazoles Pharmaceutical Science chemistry.chemical_element Pyrazole 01 natural sciences Biochemistry Article Mice Structure-Activity Relationship chemistry.chemical_compound Acetamides Drug Discovery Animals Humans Tetrazole G protein-coupled inwardly-rectifying potassium channel Molecular Biology Alkyl chemistry.chemical_classification Molecular Structure 010405 organic chemistry Activator (genetics) Aryl Organic Chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells G Protein-Coupled Inwardly-Rectifying Potassium Channels chemistry Microsomes Liver Urea Pyrazoles Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 29:791-796 |
| ISSN: | 0960-894X |
| Popis: | The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups. |
| Databáze: | OpenAIRE |
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