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
  • 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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