PAR2 Modulators Derived from GB88

被引：12

作者：

Yau, Mei-Kwan ^{[1
,2
]}

Liu, Ligong ^{[1
,2
]}

Suen, Jacky Y. ^{[1
,2
]}

Lim, Junxian ^{[1
,2
]}

Lohman, Rink-Jan ^{[1
,2
]}

Jiang, Yuhong ^{[1
,2
]}

Cotterell, Adam J. ^{[1
,2
]}

Barry, Grant D. ^{[1
,2
]}

Mak, Jeffrey Y. W. ^{[1
,2
]}

Vesey, David A. ^{[3
]}

Reid, Robert C. ^{[1
,2
]}

Fairlie, David P. ^{[1
,2
]}

机构：

[1] Univ Queensland, Ctr Inflammat & Dis Res, Div Chem & Struct Biol, Brisbane, Qld 4072, Australia

[2] Univ Queensland, ARC Ctr Excellence Adv Mol Imaging, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[3] Univ Queensland, Princess Alexandra Hosp, Dept Med, Ctr Kidney Res, Brisbane, Qld 4102, Australia

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 12期

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

Protease activated receptor 2 (PAR2); antagonist; agonist; structure activity relationship (SAR); inflammation; PROTEASE-ACTIVATED RECEPTOR-2; IN-VITRO; COLON-CANCER; ANTAGONISM; INFLAMMATION; AGONISTS; CELL; PATHOPHYSIOLOGY; PROLIFERATION; EXPRESSION;

D O I：

10.1021/acsmedchemlett.6b00306

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1179 / 1184

页数：6

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