2. Academic Validation
  3. PAR2 Modulators Derived from GB88

PAR2 Modulators Derived from GB88

  • ACS Med Chem Lett. 2016 Oct 10;7(12):1179-1184. doi: 10.1021/acsmedchemlett.6b00306.
Mei-Kwan Yau 1,  Ligong Liu 1,  Jacky Y Suen 1,  Junxian Lim 1,  Rink-Jan Lohman 1,  Yuhong Jiang 1,  Adam J Cotterell 1,  Grant D Barry 1,  Jeffrey Y W Mak 1,  David A Vesey 2,  Robert C Reid 1,  David P Fairlie 1
Affiliations

Affiliations

  • 1 Division of Chemistry and Structural Biology, Centre for Inflammation and Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
  • 2 Centre for Kidney Research, Department of Medicine, The University of Queensland, Princess Alexandra Hospital , Brisbane, Queensland 4102, Australia.
PMID: 27994760 DOI: 10.1021/acsmedchemlett.6b00306
Abstract

PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 (65) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH2 (IC50 2.2 and 0.7 μM, HT29 cells), but it was a selective PAR2 Agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed anti-inflammatory properties both in vitro and in vivo.

Keywords

Protease activated receptor 2 (PAR2); agonist; antagonist; inflammation; structure−activity relationship (SAR).

Figures