ml0c00154_si_001.pdf (3.13 MB)
Discovery of Novel Nonpeptidic PAR2 Ligands
journal contribution
posted on 2020-05-28, 13:43 authored by Ilona Klösel, Maximilian F. Schmidt, Jonas Kaindl, Harald Hübner, Dorothee Weikert, Peter GmeinerProteinase-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.
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peptidic PAR 2 agonistsIK 187crystal structurenonpeptidic PAR 2 agonistPathophysiological rolesβ- arrestin recruitmentdrug-like nonpeptidic PAR 2 ligandsnonpeptidic drugsNovel Nonpeptidic PAR 2 Ligands Proteinase-activated receptor 2G protein activationC-terminal endpeptidic agonistsG protein-coupled receptorherein-described ligand 5PAR 2Peptidic ligandsdisubstituted phenylene scaffoldsubmicromolar potency
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