Identification of orally-bioavailable antagonists of the TRPV4 ion-channel

[Display omitted] 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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-09, Vol.25 (18), p.4011-4015
Hauptverfasser:	Wei, Zhi-Liang, Nguyen, Margaret T., O’Mahony, Donogh J.R., Acevedo, Alejandra, Zipfel, Sheila, Zhang, Qingling, Liu, Luna, Dourado, Michelle, Chi, Candace, Yip, Victor, DeFalco, Jeff, Gustafson, Amy, Emerling, Daniel E., Kelly, Michael G., Kincaid, John, Vincent, Fabien, Duncton, Matthew A.J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antagonist Biological Availability Dose-Response Relationship, Drug Humans Mice Molecular Structure Pain Piperazines - administration & dosage Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Rats Rats, Wistar RN-1734 RN-9893 Structure-Activity Relationship TRPV Cation Channels - antagonists & inhibitors TRPV Cation Channels - metabolism TRPV4
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Zusammenfassung:	[Display omitted] 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.06.098