Novel Agonists and Antagonists for Human Protease Activated Receptor 2

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• 作者：Grant D. Barry ; Jacky Y. Suen ; Giang T. Le ; Adam Cotterell ; Robert C. Reid ; David P. Fairlie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 28, 2010
• 年：2010
• 卷：53
• 期：20
• 页码：7428-7440
• 全文大小：1039K
• 年卷期：v.53,no.20(October 28, 2010)
• ISSN：1520-4804

文摘

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-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 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca²⁺ release in HT29 human colorectal carcinoma cells. Antagonist GB83 (36, IC₅₀ 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-NH₂, 19). The new compounds are selective for PAR2 over PAR1, serum stable, and suitable for modulating PAR2 in disease models.