PAR2 modulators derived from GB88

Yau, Mei-Kwan, Liu, Ligong, Suen, Jacky Y., Lim, Junxian, Lohman, Rink-Jan, Jiang, Yuhong, Cotterell, Adam J., Barry, Grant D., Mak, Jeffrey Y. W., Vesey, David A., Reid, Robert C. and Fairlie, David P. (2016) PAR2 modulators derived from GB88. ACS Medicinal Chemistry Letters, 7 12: 1179-1184. doi:10.1021/acsmedchemlett.6b00306

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Author Yau, Mei-Kwan
Liu, Ligong
Suen, Jacky Y.
Lim, Junxian
Lohman, Rink-Jan
Jiang, Yuhong
Cotterell, Adam J.
Barry, Grant D.
Mak, Jeffrey Y. W.
Vesey, David A.
Reid, Robert C.
Fairlie, David P.
Title PAR2 modulators derived from GB88
Journal name ACS Medicinal Chemistry Letters   Check publisher's open access policy
ISSN 1948-5875
Publication date 2016-01-01
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acsmedchemlett.6b00306
Open Access Status File (Author Post-print)
Volume 7
Issue 12
Start page 1179
End page 1184
Total pages 6
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
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 mu M, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed antiinflammatory properties both in vitro and in vivo.
Formatted 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.
Keyword Agonist
Antagonist
Inflammation
Protease activated receptor 2 (PAR2)
Structure−activity relationship (SAR)
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1027369
1047759
CE140100011
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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Created: Mon, 05 Dec 2016, 21:42:23 EST by Susan Allen on behalf of Institute for Molecular Bioscience