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


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.

DOI: 10.1016/j.bmcl.2015.06.098

Cite this paper

@article{Wei2015IdentificationOO, title={Identification of orally-bioavailable antagonists of the TRPV4 ion-channel.}, author={Zhi-Liang Wei and Margaret Nguyen and Donogh J R O'Mahony and Alejandra Acevedo and Sheila Zipfel and Qingling Zhang and Luna Liu and Michelle Dourado and Candace L Chi and Victor Yip and Jeff Defalco and Amy Gustafson and Daniel E. Emerling and Michael G. Kelly and John W. Kincaid and Fabien Bernard Vincent and Matthew A J Duncton}, journal={Bioorganic & medicinal chemistry letters}, year={2015}, volume={25 18}, pages={4011-5} }