title: 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.
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Wei
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Margaret T
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Donogh J R
authors.initials: DJ
authors.lastname: O'Mahony
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Acevedo
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Sheila
authors.initials: S
authors.lastname: Zipfel
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Luna
authors.initials: L
authors.lastname: Liu
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dourado
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Candace
authors.initials: C
authors.lastname: Chi
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Yip
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: DeFalco
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Emerling
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States.
authors.forename: John
authors.initials: J
authors.lastname: Kincaid
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. Electronic address: fabien_vincent_us@yahoo.com.
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.affiliation: Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. Electronic address: mattduncton@yahoo.com.
authors.forename: Matthew A J
authors.initials: MA
authors.lastname: Duncton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010879:Piperazines; C000607849:RN-1665; C000607850:RN-9893; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; C486577:Trpv4 protein, rat
keywords: Antagonist; Pain; RN-1734; RN-9893; TRPV4