Synthesis and evaluation of silanediols as highly selective uncompetitive inhibitors of human neutrophil elastase

J Med Chem. 2012 Sep 13;55(17):7900-8. doi: 10.1021/jm301000k. Epub 2012 Aug 28.

Abstract

Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment of COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Silanes / chemical synthesis*
  • Silanes / pharmacology*

Substances

  • Enzyme Inhibitors
  • Silanes
  • silanediol
  • Leukocyte Elastase