选择性11β-羟化酶（CYP11B1）抑制剂加速皮肤伤口愈合
Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
作者信息
Emmerich Juliette, van Koppen Chris J, Burkhart Jens L, Engeli Roger T, Hu Qingzhong, Odermatt Alex, Hartmann Rolf W
机构信息
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123 Saarbrücken, Germany.
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.
出版信息
Eur J Med Chem. 2018 Jan 1;143:591-597. doi: 10.1016/j.ejmech.2017.11.018. Epub 2017 Nov 21.
Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
先前的研究表明，抑制皮肤中皮质醇的生物合成可加速伤口愈合。在此，对吡啶基甲基吡啶型11β-羟化酶（CYP11B1）抑制剂进行了优化，以便局部应用，避免全身副作用。由此得到的非常有效的无毒CYP11B1抑制剂14（IC = 0.8 nM）对11β-HSD1、CYP17A1和CYP19A1表现出良好的选择性。该化合物对人血浆具有高稳定性（t = > 150分钟，作为伤口液体的替代物），而对HLS9具有低稳定性（t = 19分钟），以便吸收后快速代谢清除。化合物14能够加速人体皮肤的伤口愈合。
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