[发明专利]用于治疗皮肤病的苯并恶嗪酮衍生物

说明书

技术领域

本发明涉及用于抑制皮肤蛋白酶的活性的方法和组合物，所述皮肤蛋白酶尤其是人激肽释放酶7(KLK7)，人激肽释放酶5(KLK5)和人激肽释放酶14(KLK14)。更具体地说，本发明涉及作为人皮肤激肽释放酶的选择性抑制剂的取代的3,1-苯并恶嗪-4-酮用于治疗皮肤病的用途，更具体地说，用于治疗炎性皮肤疾病，尤其是内瑟顿综合征。

背景技术

KLK7(hK7，或者角化层糜蛋白酶(SCCE)，SwissprotP49862)是显示糜蛋白酶样活性的激肽释放酶基因家族的S1丝氨酸蛋白酶。KLK7主要在皮肤中表达，且似乎在皮肤生理学中发挥重要作用(Egelrud.1993.Purification and preliminary characterization of stratum corneum chymotryptic enzyme:a proteinase that may be involved in desquamation.J.Invest.Dermatol.101,200-204；Skytt et al 1995.Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme.Biochem Biophys Res Commun.211,586-589；Yousef et al.2000.The KLK7(PRSS6)gene,encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family-genomic characterization,mapping,tissue expression and hormonal regulation.Gene.254,119-1281)。

KLK7参与在脱屑的过程中角化鳞状上皮细胞间粘性结构(cohesive structure)的降解。脱屑过程是良好调节的，而且与从头产生角质细胞成微妙的平衡，以维持角质层的恒定厚度。在这方面，KLK7据报道能够裂解角层桥粒蛋白(corneodesmosomal proteins)角化粒素和桥粒芯胶蛋白1(Simon et al.2001.Refined characterization of comeodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation.J.Biol.Chem.276,20292-20299；Caubet et al.2004.Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family,SCTE/KLK5/hK5and SCCE/KLK7/hK7.J.Invest.Dermatol.122,1235-1244；Brattsand et al.2005.A proteolytic cascade of kallikreins in the stratum corneum.J.Invest.Dermatol.124,198-203.)。此外，已经有研究表明这两种脂质加工酶β-葡糖脑苷脂酶和酸性鞘磷脂酶可以通过KLK7降解(Hachem et al.2005.Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity.J.Invest.Dermatol.125,510-520)。这两种脂质加工酶与其底物葡糖苷酰鞘氨醇类和鞘磷脂共分泌，并将这些极性脂质前体处理为他们的更加非极性产物例如神经酰胺，这些非极性产物继而掺入细胞外层状膜中。层状膜结构为功能性皮肤屏障的关键。最后，KLK7已经显示能激活促炎细胞因子前白细胞介素-1β(IL-1β)(Nylander-Lundqvist&Egelrud.1997.Formation of active IL-1βfrom pro-IL-1βcatalyzed by stratum corneum chymotryptic enzyme in vitro.Acta Derm.Venereol.77,203-206).