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
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:64 |
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| Enthalten in: |
Journal of medicinal chemistry - 64(2021), 9 vom: 13. Mai, Seite 5931-5955 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Barilli, Alessio [VerfasserIn] |
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| Links: |
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| Themen: |
Benzothiazole |
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| Anmerkungen: |
Date Completed 14.06.2021 Date Revised 14.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.1c00065 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324445563 |
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| 245 | 1 | 0 | |a From High-Throughput Screening to Target Validation |b 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 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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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| 650 | 7 | |a TRPM Cation Channels |2 NLM | |
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| 700 | 1 | |a Aldegheri, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bianchi, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Brault, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Brodbeck, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Castelletti, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Feriani, Aldo |e verfasserin |4 aut | |
| 700 | 1 | |a Lingard, Iain |e verfasserin |4 aut | |
| 700 | 1 | |a Myers, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Nola, Selena |e verfasserin |4 aut | |
| 700 | 1 | |a Piccoli, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Pompilio, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Raveglia, Luca F |e verfasserin |4 aut | |
| 700 | 1 | |a Salvagno, Cristian |e verfasserin |4 aut | |
| 700 | 1 | |a Tassini, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Virginio, Caterina |e verfasserin |4 aut | |
| 700 | 1 | |a Sabat, Mark |e verfasserin |4 aut | |
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