Discovery and kinetic evaluation of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B

Eur J Med Chem. 2011 Sep;46(9):4648-56. doi: 10.1016/j.ejmech.2011.08.005. Epub 2011 Aug 9.

Abstract

Cathepsin B is a lysosomal cysteine protease that has various physiological and pathophysiological functions. We present here the discovery of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B, starting from screening of a library of variously 2,4,6-trisubstituted 1,3,5-triazines and 1,3,5-triazin-2(1H)-ones on three different human cathepsins. The synthesis and enzymatic evaluation of a focused library of new 1,3,5-triazin-2(1H)-ones is also described. The detailed kinetics analyses have shown that these compounds can act as reversible, partial mixed-type inhibitors of cathepsin B, with K(i) and K(i)' values in the low micromolar range. The inhibitory activities of selected compounds were also assessed against two related cysteine proteases, cathepsin H and cathepsin L, to estimate their selectivity; these compounds have a selective profile for catB and catL over catH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cathepsin B / antagonists & inhibitors*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Spectrometry, Mass, Electrospray Ionization
  • Triazines / chemistry*
  • Triazines / pharmacology*

Substances

  • Enzyme Inhibitors
  • Triazines
  • Cathepsin B