2. Academic Validation
  3. Identification of orally-bioavailable antagonists of the TRPV4 ion-channel

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.
Zhi-Liang Wei 1,  Margaret T Nguyen 1,  Donogh J R O'Mahony 1,  Alejandra Acevedo 1,  Sheila Zipfel 1,  Qingling Zhang 1,  Luna Liu 1,  Michelle Dourado 1,  Candace Chi 1,  Victor Yip 1,  Jeff DeFalco 1,  Amy Gustafson 1,  Daniel E Emerling 1,  Michael G Kelly 1,  John Kincaid 1,  Fabien Vincent 2,  Matthew A J Duncton 3
Affiliations

Affiliations

  • 1 Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
  • 2 Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 3 Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 26235950 DOI: 10.1016/j.bmcl.2015.06.098
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.

Keywords

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

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