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.
Gmeiner, Peter,Hübner, Harald,Kaindl, Jonas,Kl?sel, Ilona,Schmidt, Maximilian F.,Weikert, Dorothee
supporting information
p. 1316 - 1323
(2020/07/04)
An efficient synthesis of 2-(((9- fluorenylmethoxycarbonyl)amino)methyl)benzoic acid
An efficient, two-step synthesis of the title compound 3 in 61% overall yield is presented. The synthesis involves hydrazine removal of the N- phthalimide protecting group of α-phthalimido-o-toluic acid (6), followed by N-Fmoc formation with (9-fluorenylm
Sun, Jung-Hui,Daneker, Wayne F.
p. 4525 - 4530
(2007/10/03)
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