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

Bioorg Med Chem Lett. 2015 Sep 15;25(18):4011-5. doi: 10.1016/j.bmcl.2015.06.098. Epub 2015 Jul 6.


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.

Keywords: Antagonist; Pain; RN-1734; RN-9893; TRPV4.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Molecular Structure
  • Piperazines / administration & dosage*
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism


  • Piperazines
  • RN-1665
  • RN-9893
  • TRPV Cation Channels
  • TRPV4 protein, human
  • Trpv4 protein, mouse
  • Trpv4 protein, rat