title: Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists.
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 2.8μM. 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.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Cho
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Ji Hyoun
authors.initials: JH
authors.lastname: Cha
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Jinsook
authors.initials: J
authors.lastname: Kwak
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Dohee
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea; Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejeon 305-350, Republic of Korea.
authors.forename: TaeHun
authors.initials: T
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejeon 305-350, Republic of Korea.
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Global Medical Science, Sungshin University, Seoul 142-732, Republic of Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejeon 305-350, Republic of Korea.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea; Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejeon 305-350, Republic of Korea. Electronic address: anpae@kist.re.kr.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000586:Amination; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D015232:Dinoprostone / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000276:immunology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011799:Quinazolines; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone
keywords: Anti-inflammation agent; G protein-coupled receptor; Protease-activated receptor 2; Sepsis