2. Academic Validation
  3. Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate

Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate

  • J Med Chem. 2007 Jul 26;50(15):3515-27. doi: 10.1021/jm070190p.
Elizabeth M Doherty 1,  Christopher Fotsch,  Anthony W Bannon,  Yunxin Bo,  Ning Chen,  Celia Dominguez,  James Falsey,  Narender R Gavva,  Jodie Katon,  Thomas Nixey,  Vassil I Ognyanov,  Liping Pettus,  Robert M Rzasa,  Markian Stec,  Sekhar Surapaneni,  Rami Tamir,  Jiawang Zhu,  James J S Treanor,  Mark H Norman
Affiliations

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA.
PMID: 17585750 DOI: 10.1021/jm070190p
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.

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