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

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

doi:10.1016/j.ejmech.2017.11.018

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

Eur J Med Chem. 2018 Jan 1:143:591-597. doi: 10.1016/j.ejmech.2017.11.018. Epub 2017 Nov 21.

Authors

Juliette Emmerich¹, Chris J van Koppen², Jens L Burkhart², Roger T Engeli³, Qingzhong Hu¹, Alex Odermatt³, Rolf W Hartmann⁴

Affiliations

¹ 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.
² Pharmaceutical and Medicinal Chemistry, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.
³ Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
⁴ 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. Electronic address: rolf.hartmann@helmholtz-hzi.de.

PMID: 29207342
DOI: 10.1016/j.ejmech.2017.11.018

Abstract

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 (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.

Keywords: 11β-hydroxylase (CYP11B1) inhibitors; 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); Chronic wounds; Topical application; Wound healing.

MeSH terms

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
Wound Healing / drug effects*

Substances

Enzyme Inhibitors
Pyridines
Steroid 11-beta-Hydroxylase
pyridine