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Discovery of Novel Nonpeptidic PAR2 Ligands.

ABSTRACT: Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and show poor bioavailability, and only a few approaches toward drug-like nonpeptidic PAR2 ligands have been described. The herein-described ligand 5a (IK187) is a nonpeptidic PAR2 agonist with submicromolar potency in a functional assay reflecting G protein activation. The ligand also showed substantial β-arrestin recruitment. The development of the compound was guided by the crystal structure of PAR2, when the C-terminal end of peptidic agonists was replaced by a small molecule based on a disubstituted phenylene scaffold. IK187 shows preferable metabolic stability and may serve as a lead compound for the development of nonpeptidic drugs addressing PAR2.

SUBMITTER: Klosel I

PROVIDER: S-EPMC7294704 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of Novel Nonpeptidic PAR2 Ligands.

Klösel Ilona I Schmidt Maximilian F MF Kaindl Jonas J Hübner Harald H Weikert Dorothee D Gmeiner Peter P

ACS medicinal chemistry letters 20200522 6

Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and show poor bioavailability, and only a few approaches toward drug-like nonpeptidic PAR2 ligands have been described. The herein-described ligand <b>5a</b> (I ...[more]

PMID: 32551018

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