Emmerich Juliette, van Koppen Chris J, Burkhart Jens L, Engeli Roger T, Hu Qingzhong, Odermatt Alex, Hartmann Rolf W
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.
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。
