Discovery of ‘molecular switches’ within a GIRK activator scaffold that afford selective GIRK inhibitors
| Autor: | Yu Du, Wandong Wen, Wenjun Wu, Craig W. Lindsley, Kristian Kaufmann, Ian M. Romaine, Gary A. Sulikowski, C. David Weaver |
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| Rok vydání: | 2013 |
| Předmět: |
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Molecular Scaffold Stereochemistry Clinical Biochemistry Pharmaceutical Science Plasma protein binding Biochemistry Article Structure-Activity Relationship Drug Discovery Structure–activity relationship G protein-coupled inwardly-rectifying potassium channel Molecular Biology Biotransformation Molecular switch Molecular Structure urogenital system Activator (genetics) Chemistry Drug discovery Organic Chemistry G Protein-Coupled Inwardly-Rectifying Potassium Channels Pharmaceutical Preparations Molecular Medicine Selectivity Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:4562-4566 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.06.023 |
| Popis: | This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity. |
| Databáze: | OpenAIRE |
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