Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

本研究报道了通过铃木交叉偶联（Suzuki cross-coupling）模块化合成的新型联芳基酰胺类11β-羟类固醇脱氢酶1 (11β-hydroxysteroid dehydrogenase 1, 11β-HSD1) 抑制剂的活性与选择性评价工作。研究筛选得到多个可在纳摩尔浓度下抑制11β-HSD1活性的化合物，其中化合物2b、3e、7b与12e可选择性靶向抑制11β-HSD1，相较于11β-HSD2、17β-HSD1及17β-HSD2表现出优异的亚型选择性。此类抑制剂在表达重组11β-HSD1的完整HEK-293细胞，以及表达内源性11β-HSD1的原代人角质形成细胞中，均展现出强效的酶活性抑制效果。此外，本研究针对化合物2b、3e及12e在人体皮肤活检组织中的活性进行了测试，结果显示这三种化合物可部分阻断可的松与紫外线介导的胶原蛋白含量降低现象。综上，可针对此类化合物的11β-HSD1抑制作用开展进一步研究，以延缓甚至阻断紫外线介导的皮肤损伤与皮肤衰老进程。