Design, synthesis and biological evaluation of novel and potent protease-activated receptor 2(PAR) antagonists for treating arthritis

초록

Protease-activated receptor 2 (PAR2) is the second number of a novel family of seven-transmembrane Gprotein-coupled receptors, PARs. They are mainly expressed in platelets, but also on endothelial cells, myocytes and neurons. Activation of PAR2 is initiated through a proteolytic cleavage of serine proteases such as trypsin or b-tryptase from mast cells, exposing a tethered ligand domain which binds and activates the cleaved receptor. This receptor regulates various physiological functions including vasoregulation, arteriolar dilation, degranulation of mast cells and cell growth to inflammation. Initial observations of PAR2 knock-down mice indicated that the receptors may be useful therapeutic agents for the treatment of human diseases such as arthritis. Therefore, PAR-2 is targeted to develop as inflammatory joint disease drug. A novel series of 64 quinazoline and 2 pyrimidine derivatives were designed and synthesized as PAR2 antagonist. The synthesized 6-methoxy-quinazoline compounds showed reasonable inflammatory inhibition activity against various inflammatory cell lines. The detailed design, synthesis and biological evaluation of PAR2 antagonists as inflammatory joint disease drugs will be presented.