Potent 11β-hydroxylase inhibitors with inverse metabolic stability in human plasma and hepatic S9 fractions to promote wound healing

J Med Chem. 2014 Sep 25;57(18):7811-7. doi: 10.1021/jm501004t. Epub 2014 Sep 8.

Abstract

Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50 = 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2 ≫ 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / metabolism
  • Aromatase Inhibitors / blood
  • Aromatase Inhibitors / metabolism
  • Aromatase Inhibitors / pharmacology
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors
  • Cytochrome P-450 Enzyme Inhibitors / blood
  • Cytochrome P-450 Enzyme Inhibitors / metabolism*
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Drug Design*
  • Drug Stability
  • Humans
  • Liver / metabolism*
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors*
  • Wound Healing / drug effects*

Substances

  • Aromatase Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Aromatase
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase