Benzylamide antagonists of protease activated receptor 2 with anti-inflammatory activity

Bioorg Med Chem Lett. 2016 Feb 1;26(3):986-991. doi: 10.1016/j.bmcl.2015.12.048.

Mei-Kwan Yau ¹, Ligong Liu ¹, Junxian Lim ¹, Rink-Jan Lohman ¹, Adam J Cotterell ¹, Jacky Y Suen ¹, David A Vesey ², Robert C Reid ¹, David P Fairlie ³

Affiliations

1 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
2 Centre for Kidney Disease Research, Department of Medicine, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
3 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: d.fairlie@uq.edu.au.

PMID: 26725028 DOI: 10.1016/j.bmcl.2015.12.048

Abstract

Activation of protease activated receptor 2 (PAR2) has been implicated in inflammatory and metabolic disorders and its inhibition may yield novel therapeutics. Here, we report a series of PAR2 antagonists based on C-terminal capping of 5-isoxazolyl-L-cyclohexylalanine-L-isoleucine, with benzylamine analogues being effective new PAR2 antagonists. 5-Isoxazolyl-L-cyclohexylalanine-L-isoleucine-2-methoxybenzylamine (10) inhibited PAR2-, but not PAR1-, induced release of CA(2+) (IC50 0.5 μM) in human colon cells, IL-6 and TNFα secretion (IC50 1-5 μM) from human kidney cells, and was anti-inflammatory in acute rat paw inflammation (ED50 5 mg/kg sc). These findings show that new benzylamide antagonists of PAR2 have anti-inflammatory activity.

Keywords

Agonist; Antagonist; Benzylamine; Inflammation; Protease activated receptor 2 (PAR2).

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