title: Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.
abstract: A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Bo
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.forename: James
authors.initials: J
authors.lastname: Falsey
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Jodie
authors.initials: J
authors.lastname: Katon
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Vassil I
authors.initials: VI
authors.lastname: Ognyanov
authors.forename: Liping
authors.initials: L
authors.lastname: Pettus
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: Jiawang
authors.initials: J
authors.lastname: Zhu
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004355:Drug Stability; D000882:Haplorhini; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010147:Pain Measurement; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000700:Analgesics; D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002118:Calcium