Novel Vanilloid Receptor-1 Antagonists: 2. Structure−Activity Relationships of 4-Oxopyrimidines Leading to the Selection of a Clinical Candidate

Citations Over TimeTop 10% of 2007 papers

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.

Related Papers

• → N-palmitoyl-vanillamide (palvanil) is a non-pungent analogue of capsaicin with stronger desensitizing capability against the TRPV1 receptor and anti-hyperalgesic activity(2011)39 cited
• → Capsaicin-induced inhibition of platelet aggregation is not mediated by transient receptor potential vanilloid type 1(2011)25 cited
• → Understanding the Molecular Determinants of Capsaicin Mode of Action(2015)1 cited
• → Inhibition of platelet aggregation by capsaicin is not mediated by the TRPV1 receptor(2009)
• → Effects of vanilloid analogues structurally related to capsaicin on the TRPV1 channel(2022)