Identification of orally-bioavailable antagonists of the TRPV4 ion-channel
| Autor: | Fabien Vincent, Michelle Dourado, Daniel Emerling, Luna Liu, Victor Yip, Margaret Nguyen, Zhi-Liang Wei, Zipfel Sheila, Candace Chi, Amy Gustafson, Jeff DeFalco, Michael G. Kelly, John Kincaid, Qingling Zhang, Donogh J R O'Mahony, Matthew A.J. Duncton, Alejandra Acevedo |
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| Rok vydání: | 2015 |
| Předmět: |
TRPV4
TRPV3 Stereochemistry Clinical Biochemistry TRPV1 Administration Oral Biological Availability TRPV Cation Channels Pharmaceutical Science Pharmacology Biochemistry Piperazines Mice Structure-Activity Relationship In vivo Drug Discovery TRPM8 Animals Humans Rats Wistar Receptor Molecular Biology Ion channel Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Rats Bioavailability Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:4011-4015 |
| ISSN: | 0960-894X |
| Popis: | Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-1665 23 and RN-9893 26, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-9893 26, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications. |
| Databáze: | OpenAIRE |
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