title: Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues of trans-cinnamides.
abstract: The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. markn@amgen.com
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Jiawang
authors.initials: J
authors.lastname: Zhu
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Bo
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Partha
authors.initials: P
authors.lastname: Chakrabarti
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Vassil I
authors.initials: VI
authors.lastname: Ognyanov
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Markian
authors.initials: M
authors.lastname: Stec
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006930:Hyperalgesia / Q000517:prevention & control; D007275:Injections, Intravenous; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013816:Thermodynamics
chemical_list: C523407:7-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoline; D000634:Aminoquinolines; D000700:Analgesics; C523408:N-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)quinolin-7-amine; D011743:Pyrimidines; D011804:Quinolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat