Potent Agonists of the Protease Activated Receptor 2 (PAR2)

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• 作者：Scott Boitano ; Andrea N. Flynn ; Stephanie M. Schulz ; Justin Hoffman ; Theodore J. Price ; Josef Vagner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1308-1313
• 全文大小：815K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

Novel peptidomimetic pharmacophores to PAR₂ were designed based on the known activating peptide SLIGRL-NH₂. A set of 15 analogues was evaluated with a model cell line (16HBE14o-) that highly expresses PAR₂. Cells exposed to the PAR₂ activating peptide with N-terminal 2-furoyl modification (2-furoyl-LIGRLO-NH₂) initiated increases in intracellular calcium concentration ([Ca²⁺]_i EC₅₀ = 0.84 渭M) and in vitro physiological responses as measured by the xCELLigence real time cell analyzer (RTCA EC₅₀ = 138 nM). We discovered two selective PAR₂ agonists with comparable potency: compound 1 (2-aminothiazol-4-yl; Ca²⁺ EC₅₀ = 1.77 渭M, RTCA EC₅₀ = 142 nM) and compound 2 (6-aminonicotinyl; Ca²⁺ EC₅₀ = 2.60 渭M, RTCA EC₅₀ = 311 nM). Unlike the previously described agonist, these novel agonists are devoid of the metabolically unstable 2-furoyl modification and thus provide potential advantages for PAR₂ peptide design for in vitro and in vivo studies. The novel compounds described herein also serve as a starting point for structure鈭抋ctivity relationship (SAR) design and are, for the first time, evaluated via a unique high throughput in vitro physiological assay. Together these will lead to discovery of more potent agonists and antagonists of PAR₂.