Potent Agonists of the Protease Activated Receptor 2 (PAR2)

S Boitano, AN Flynn, SM Schulz… - Journal of medicinal …, 2011 - ACS Publications
S Boitano, AN Flynn, SM Schulz, J Hoffman, TJ Price, J Vagner
Journal of medicinal chemistry, 2011ACS Publications
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 μM) and in vitro physiological
responses as measured by the xCELLigence real time cell analyzer (RTCA EC50= 138 nM) …
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 μM) 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 μM, RTCA EC50 = 142 nM) and compound 2 (6-aminonicotinyl; Ca2+ EC50 = 2.60 μM, 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−activity 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.
ACS Publications