7-Hydroxynaphthalen-1-yl-urea and -amide antagonists of human vanilloid receptor 1

A series of structurally simple 7-hydroxynaphthalenyl ureas and amides were discovered to be potent ligands of human vanilloid receptor 1 (VR1). 1-(7-Hydroxynaphthalen-1-yl)-3-(4-trifluoromethylbenzyl)urea 5f exhibited nanomolar binding affinity (Ki=1.0 nM) and upon capsaicin challenge, behaved as a potent functional antagonist (IC50=4 nM). The synthesis and structure–activity relationships (SARs) for the series are described.