Potent agonists of the protease activated receptor2 (PAR2)

Scott Boitano, Andrea N. Flynn, Stephanie M. Schulz, Justin Hoffman, Theodore J. Price, Josef Vagner

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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 PAR 2. 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 PAR 2.

Original languageEnglish (US)
Pages (from-to)1308-1313
Number of pages6
JournalJournal of Medicinal Chemistry
Volume54
Issue number5
DOIs
StatePublished - Mar 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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