Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists

Title
Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists
Authors
조남철차지현김효진곽진숙김도희서승환신지선김태훈박기덕이지연노경태김윤경이경태배애님
Keywords
Protease-activated receptor 2; G protein-coupled receptor; Anti-inflammation agent
Issue Date
2015-11
Publisher
Bioorganic & medicinal chemistry
Citation
VOL 23, 7717-7727
Abstract
Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8 μM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo.
URI
http://pubs.kist.re.kr/handle/201004/58247
ISSN
09680896
Appears in Collections:
KIST Publication > Article
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