89795-79-9Relevant articles and documents
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
Barilli, Alessio,Aldegheri, Laura,Bianchi, Federica,Brault, Laurent,Brodbeck, Daniela,Castelletti, Laura,Feriani, Aldo,Lingard, Iain,Myers, Richard,Nola, Selena,Piccoli, Laura,Pompilio, Daniela,Raveglia, Luca F.,Salvagno, Cristian,Tassini, Sabrina,Virginio, Caterina,Sabat, Mark
, p. 5931 - 5955 (2021/06/01)
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.
