Accelerated skin wound healing by selective 11β²-Hydroxylase (CYP11B1) inhibitors
European journal of medicinal chemistry
Pages / Article-Number
Dose-Response Relationship, Drug; Enzyme Inhibitors, chemical synthesis, chemistry, pharmacology; Humans; Molecular Structure; Pyridines, chemical synthesis, chemistry, pharmacology; Skin, drug effects; Steroid 11-beta-Hydroxylase, antagonists & inhibitors, metabolism; Structure-Activity Relationship; Wound Healing, drug effects
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; 50; = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t; 1/2; = > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t; 1/2; = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.