2. Academic Validation
  3. 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

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. 2021 May 13;64(9):5931-5955. doi: 10.1021/acs.jmedchem.1c00065.
Alessio Barilli 1,  Laura Aldegheri 1,  Federica Bianchi 1,  Laurent Brault 1,  Daniela Brodbeck 1,  Laura Castelletti 1,  Aldo Feriani 1,  Iain Lingard 1,  Richard Myers 2,  Selena Nola 1,  Laura Piccoli 1,  Daniela Pompilio 1,  Luca F Raveglia 1,  Cristian Salvagno 1,  Sabrina Tassini 1,  Caterina Virginio 1,  Mark Sabat 2
Affiliations

Affiliations

  • 1 Aptuit, an Evotec Company, Via Alessandro Fleming, 4, Verona 37135, Italy.
  • 2 Takeda Pharmaceuticals, 9625 Towne Centre Drive, San Diego, California 92121, United States.
PMID: 33890770 DOI: 10.1021/acs.jmedchem.1c00065
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.

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