1,2,4-Triazole derivatives as transient inactivators of kallikreins involved in skin diseases

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4547-51. doi: 10.1016/j.bmcl.2013.06.039. Epub 2013 Jun 24.

Abstract

We describe here 1,2,4-triazoles derivatives identified as transient inactivators acting at the nanomolar level on human kallikreins (hK5, hK7 and hK14) and matriptase. Both the nature of the targeted enzymes and structural variations of the inhibitors influence the life-times of acyl-enzymes. These nonpeptidic, transient and low-molecular-weight inhibitors were found to be noncytotoxic against healthy human keratinocytes. These molecules may be useful to counteract dysregulated proteolytic cascades observed in dermatological disorders such as Netherton syndrome.

Keywords: 3-amino-7-methyl-coumarin; AMC; Acyl-enzymes; DMSO; HTS; Inhibitors; Kallikreins; LEKTI; Matriptase; Netherton syndrome; Transient inactivators; dimethyl sulfoxide; hK; high throughput screening; human kallikrein; lympho-epithelial Kazal-type inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Keratinocytes / drug effects*
  • Skin Diseases / drug therapy
  • Triazoles / chemistry*
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use

Substances

  • Enzyme Inhibitors
  • Triazoles
  • 1,2,4-triazole
  • Kallikreins