Cho, Nam-Chul Cha, Ji Hyoun Kim, Hyojin Kwak, Jinsook Kim, Dohee Seo, Seung-Hwan Shin, Ji-Sun Kim, TaeHun Park, Ki Duk Lee, Jiyoun No, Kyoung Tai Kim, Yun Kyung Lee, Kyung-Tae Pae, Ae Nim 2024-01-20T05:31:06Z 2024-01-20T05:31:06Z 2021-09-03 2015-12-15 0968-0896 https://pubs.kist.re.kr/handle/201004/124626 Protease-activated receptor 2 (PAR(2)) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR(2) 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 PAR(2) 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 mu M. Binding modes of the newly identified PAR(2) antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR(2) homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E-2 (PGE(2)), interleukin- 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) through the regulation of various intracellular signaling pathways involving nuclear factor-kappa B (NF-kappa B), 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 PAR(2) antagonists with anti-inflammatory activity in vitro and in vivo. (c) 2015 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD ARRESTIN-DEPENDENT ENDOCYTOSIS EPITHELIAL-CELLS INFLAMMATORY RESPONSES PROTECTS MICE PAR2 INHIBITION BETA-ARRESTIN-1 EXPRESSION PATHWAYS REQUIRES Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR(2)) antagonists Article 10.1016/j.bmc.2015.11.016 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.23, no.24, pp.7717 - 7727 BIOORGANIC & MEDICINAL CHEMISTRY 23 24 7717 7727 scie scopus 000366645600021 2-s2.0-84949676785 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article ARRESTIN-DEPENDENT ENDOCYTOSIS EPITHELIAL-CELLS INFLAMMATORY RESPONSES PROTECTS MICE PAR2 INHIBITION BETA-ARRESTIN-1 EXPRESSION PATHWAYS REQUIRES Protease-activated receptor 2 G protein-coupled receptor Anti-inflammation agent Sepsis