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 (K(i)=1.0nM) and upon capsaicin challenge, behaved as a potent functional antagonist (IC(50)=4nM). The synthesis and structure-activity relationships (SARs) for the series are described.
McDonnell
Mark E
ME
Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA.
Zhang
Sui Po
SP
Nasser
Nadia
N
Dubin
Adrienne E
AE
Dax
Scott L
SL
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009284:Naphthols / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050916:TRPV Cation Channels; D014508:Urea / Q000737:chemistry* / Q000378:metabolism
D000577:Amides; D009284:Naphthols; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea