Sang Eun Lee, et al. Among the several approaches for PAR-2 antagonizing treatment, use of small molecule PAR-2 specific antago- nist seems to be the most promising method. However, while several PAR-1 specific antagonists have already been reported, the lack of a specific, potent PAR-2 antagonist has hampered more detailed investigation of the role of PAR-2 in various diseases and its practical application. Recently, however, a few PAR-2 specific antagonists and their in vivo and in vitro effects have been reported. ENMD- 1,068 (N1-3-methylbutyryl-N4-6-aminohexanoyl-pipera- zine) was the first reported PAR-2 specific antagonist, and its anti-inflammatory activity was evaluated using both in vivo and ex vivo models. In a carrageenan/kaolin (C/K)- induced arthritis animal model, intraperitoneal injection of ENMD-1,068 showed significant inhibition of joint swell- ing109 and in ex vivo studies using rheumatoid arthritis syno- vium and cultured synovial fibroblasts, ENMD-1,068 also showed inhibitory effects on proinflammatory cytokine pro- duction in a dose-dependent manner.110 In addition, we have shown that topical application of ENMD-1,068 on barrier disrupted skin significantly accelerated barrier recovery rate, which also suggest the potential application of ENMD-1,068 as a topical agent.12 However, its low po- tency ranging low millimolar concentration has made it impractical for therapeutic application. More recently, Kanke, et al.111 have reported several pepti- domimetic compounds as having PAR-2 antagonistic activities. Among the compounds, it was reported that K- 14585 {N-[1-(2, 6-dichlorophenyl)methyl]-3-(1-pyrroli- dinylmethyl)-1H-indol-5-yl)aminocarbonyl}-glycine-L- lysinyl-Lphenylalanyl-N-benzhydrylamide) showed the most potent antagonist activity against PAR-2 activating peptide induced cellular responses. Ex vivo responses, such as rat-isolated aorta relaxation, and in vivo responses, such as plasma extravasation in the dorsal skin of guinea pigs and saliva secretion in anaesthetized mice, were also inhibited by a systemic injection of K-14585. Interestingly, it was observed that while K-14585 significantly inhibited the activating peptide-induced PAR-2 activation signaling, serine protease (trypsin)-induced signaling was affected to a much lesser extent. It was suggested that there may be some structural differences between the activating peptide binding site and tethered ligand binding site; this distinc- tion need a further investigation. More interestingly, in a study of K-14585-induced cellular signaling, higher con- centrations of K-14585 showed agonistic activity, which still needs further investigation.112 Given these results, prac- tical therapeutic application of K-14585 is currently not achievable. Currently, the authors are investigating a new PAR-2 antagonist. In a series of in vitro and in vivo studies, the new PAR-2 antagonist, NPS-1577, has shown potential anti- inflammatory activity as well as skin barrier improving activity and anti-hyperproliferative activity on the epidermis (paper in preparation). While detailed investigations related to the action mechanism are currently being performed, NPS-1577 could potentially be used as the first practical PAR-2 antagonist for therapeutic use in the near future. ACKNOWLEDGEMENTS This work was financially supported by the Ministry of Knowledge Economy (MKE) and Korea Institute for Advancement of Technology (KIAT) through the Research and Development for Regional Industry. REFERENCES 1. Richard I. The genetic and molecular bases of monogenic disorders affecting proteolytic systems. J Med Genet 2005;42: 529-39. 2. Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol 2008;153 Suppl 1:S263-82. 3. Brattsand M, Egelrud T. Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J Biol Chem 1999;274:30033-40. 4. Hansson L, Strömqvist M, Bäckman A, Wallbrandt P, Carlstein A, Egelrud T. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J Biol Chem 1994;269:19420-6. 5. 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