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.
J Med Chem
; 64(9): 5931-5955, 2021 05 13.
Article
em En
| MEDLINE
| ID: mdl-33890770
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trato Gastrointestinal
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Benzotiazóis
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Canais de Cátion TRPM
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Ensaios de Triagem em Larga Escala
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article