title: Benzylamide antagonists of protease activated receptor 2 with anti-inflammatory activity.
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.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Mei-Kwan
authors.initials: MK
authors.lastname: Yau
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Cotterell
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.affiliation: Centre for Kidney Disease Research, Department of Medicine, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.affiliation: 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.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007532:Isoleucine / Q000737:chemistry; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D044464:Receptor, PAR-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; D007532:Isoleucine; C028544:cyclohexylalanine; D010649:Phenylalanine; D002118:Calcium
keywords: Agonist; Antagonist; Benzylamine; Inflammation; Protease activated receptor 2 (PAR2)