Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors

• Published in: European journal of medicinal chemistry 2018-01, Vol.143, p.591-597
• Main Authors: Emmerich, Juliette, van Koppen, Chris J., Burkhart, Jens L., Engeli, Roger T., Hu, Qingzhong, Odermatt, Alex, Hartmann, Rolf W.
• Format: Article
• Language: English
• Subjects: 11β-hydroxylase (CYP11B1) inhibitors; 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); Chronic wounds; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Molecular Structure; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Skin - drug effects; Steroid 11-beta-Hydroxylase - antagonists & inhibitors; Steroid 11-beta-Hydroxylase - metabolism; Structure-Activity Relationship; Topical application; Wound healing; Wound Healing - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.018

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 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin. [Display omitted] •Novel CYP11B1 inhibitors for topical treatment of chronic wounds synthesized.•Selectivity over 11β-HSD1 and CYP19A1 obtained.•Compounds are metabolically instable to avoid systemic effects.•Acceleration of wound healing in human skin (ex vivo) demonstrated.