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

Abstract 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.