From High-Throughput Screening to Target Validation: Benzo[d]isothiazoles as Potent and Selective Agonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 5 Possessing In Vivo Gastrointestinal Prokinetic Activity in Rodents
| Autor: | Daniela Pompilio, Sabrina Tassini, Laura Piccoli, Alessio Barilli, Aldo Feriani, Daniela Brodbeck, Laura Castelletti, Raveglia Luca Francesco, Laurent Brault, Iain Lingard, Laura Aldegheri, Federica Bianchi, Mark Sabat, Richard M. Myers, Caterina Virginio, Selena Nola, Cristian Salvagno |
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| Rok vydání: | 2021 |
| Předmět: |
Agonist
0303 health sciences Isothiazole medicine.drug_class High-throughput screening Hit to lead Pharmacology 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Transient receptor potential channel chemistry In vivo Drug Discovery medicine Molecular Medicine TRPM5 Drug metabolism 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 64:5931-5955 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00065 |
| Popis: | Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a nonselective monovalent cation channel activated by intracellular Ca2+ increase. Within the gastrointestinal system, TRPM5 is expressed in the stoma, small intestine, and colon. In the search for a selective agonist of TRPM5 possessing in vivo gastrointestinal prokinetic activity, a high-throughput screening was performed and compound 1 was identified as a promising hit. Hit validation and hit to lead activities led to the discovery of a series of benzo[d]isothiazole derivatives. Among these, compounds 61 and 64 showed nanomolar activity and excellent selectivity (>100-fold) versus related cation channels. The in vivo drug metabolism and pharmacokinetic profile of compound 64 was found to be ideal for a compound acting locally at the intestinal level, with minimal absorption into systemic circulation. Compound 64 was tested in vivo in a mouse motility assay at 100 mg/kg, and demonstrated increased prokinetic activity. |
| Databáze: | OpenAIRE |
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