Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 20, Pages 7428-7440Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100984y
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Funding
- Australian Research Council (ARC) [FF668733, DP1093245]
- National Health and Medical Research Council of Australia [569595, APP 1000745]
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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., SLICK V-NH2, SLIGRL-NH2), 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, EC50 0.28 mu M) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells. Antagonist GB83 (36, IC50 2 mu M) 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-NH2, 19). The new compounds are selective for PAR2 over PAR1, serum stable, and suitable for modulating PAR2 in disease models.
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