Potent agonists of the protease activated receptor2 (PAR2)

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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

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Peptide Hydrolases
Peptides
Peptidomimetics
Structure-Activity Relationship
Calcium
Cell Line
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Potent agonists of the protease activated receptor2 (PAR2). / Boitano, Scott A; Flynn, Andrea N.; Schulz, Stephanie M.; Hoffman, Justin; Price, Theodore J.; Vagner, Josef.

In: Journal of Medicinal Chemistry, Vol. 54, No. 5, 10.03.2011, p. 1308-1313.

Research output: Contribution to journalArticle

Boitano, Scott A ; Flynn, Andrea N. ; Schulz, Stephanie M. ; Hoffman, Justin ; Price, Theodore J. ; Vagner, Josef. / Potent agonists of the protease activated receptor2 (PAR2). In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 5. pp. 1308-1313.
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