title: Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides.
abstract: The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. edoherty@amgen.com
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Bo
authors.forename: Partha P
authors.initials: PP
authors.lastname: Chakrabarti
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Narender
authors.initials: N
authors.lastname: Gavva
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.forename: John
authors.initials: J
authors.lastname: Kincaid
authors.forename: Lana
authors.initials: L
authors.lastname: Klionsky
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Vassil I
authors.initials: VI
authors.lastname: Ognyanov
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Jiawang
authors.initials: J
authors.lastname: Zhu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001671:Biochemistry / Q000379:methods; D001682:Biological Availability; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002934:Cinnamates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels
chemical_list: D002934:Cinnamates; D007473:Ion Channels; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin; D002118:Calcium