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

Nam Chul Cho, Ji Hyoun Cha, Hyojin Kim, Jinsook Kwak, Dohee Kim, Seung Hwan Seo, Ji Sun Shin, Taehun Kim, Ki Duk Park, Jiyoun Lee, Kyoung Tai No, Yun Kyung Kim, Kyung Tae Lee, Ae Nim Pae

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7717-7727
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number24
Publication statusPublished - 2015 Dec 15

Bibliographical note

Funding Information:
This work was supported by Korea Institute of Science and Technology ( 2E25240 and 2E25473 ), Republic of Korea.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


Dive into the research topics of 'Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists'. Together they form a unique fingerprint.

Cite this