AC-55541 is a small-molecule protease-activated receptor 2 (PAR2) agonist and activates PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca(2+) mobilization assays, with potencies ranging from 200 to 1000 nM.
Protease activated receptors (PARs) are a family of four G-protein-coupled receptors (PAR1, PAR2, PAR3, and PAR4) that are self-activated by tethered peptide ligands exposed by proteolytic cleavage of the extracellular amino terminus. PAR2 receptors have been implicated in numerous physiological processes necessitating therapeutic intervention, especially pain and inflammation and syndromes with a strong inflammatory component, including colitis, gastritis, pancreatitis, asthma and pulmonary disease. AC-55541 is a highly selective PAR2 agonist with pEC50 value of 6.7. Concentration-response experiments demonstrated that AC-55541 stimulated cellular proliferation in a PAR2-specific manner. The potencies of AC-55541 in the cellular proliferation assay was approximately 200 nM at the protease-insensitive mutant PAR2 S37P , and was virtually the same at wild-type PAR2 receptors. In the PI hydrolysis assays, AC-55541 had potency of approximately 1 to 3M. In the Ca2+ mobilization assay, AC-55541 had potency of approximately 250 nM. Intraperitoneal administration of AC-55541 resulted in peak plasma concentration of 1035 ng/ml at 50 min in male Sprague-Dawley rats. The elimination half-live of AC-55541 was 6.1 h. AC-55541 was reasonably stable to metabolism in the presence of liver microsomes, with values of 6 and 19 μL/min/mg for AC-55541 in human and rat liver microsomes, respectively. Moreover, intrapaw administration of AC-55541 resulted in hind paw edema and thermal hyperalgesia at doses as low as 30 ng[1].
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