Novel agonists and antagonists for human protease activated receptor 2

J Med Chem. 2010 Oct 28;53(20):7428-40. doi: 10.1021/jm100984y.


Human protease activated receptor 2 (PAR2) is a G protein-coupled receptor that is associated with inflammatory diseases and cancers. PAR2 is activated by serine proteases that cleave its N-terminus and by synthetic peptides corresponding to the new N-terminus. Peptide agonists are widely used to characterize physiological roles for PAR2 but typically have low potency (e.g., SLIGKV-NH(2), SLIGRL-NH(2)), uncertain target selectivity, and poor bioavailability, limiting their usefulness for specifically interrogating PAR2 in vivo. Structure-activity relationships were used to derive new PAR2 agonists and antagonists containing nonpeptidic moieties. Agonist GB110 (19, EC(50) 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca(2+) release in HT29 human colorectal carcinoma cells. Antagonist GB83 (36, IC(50) 2 μM) is the first compound at micromolar concentrations to reversibly inhibit PAR2 activation by both proteases and other PAR2 agonists (e.g., trypsin, 2f-furoyl-LIGRLO-NH(2), 19). The new compounds are selective for PAR2 over PAR1, serum stable, and suitable for modulating PAR2 in disease models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Cell Line
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Drug Stability
  • Humans
  • In Vitro Techniques
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Receptor, PAR-2 / agonists*
  • Receptor, PAR-2 / antagonists & inhibitors*
  • Serum


  • 5-isoxazoyl-cyclohexylalanyl-isoleucyl-(3-(aminomethyl)phenyl)-(4-(aminomethyl)piperidin-1-yl)methanone
  • 5-isoxazoyl-cyclohexylalanyl-isoleucyl-spiroindane-1,4'-piperidine
  • Dipeptides
  • Isoxazoles
  • Oligopeptides
  • Receptor, PAR-2
  • Calcium