Discovery libraries targeting the major enzyme classes: the serine hydrolases

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3807-13. doi: 10.1016/j.bmcl.2014.06.063. Epub 2014 Jun 27.

Abstract

Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent structural diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki=100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas.

Keywords: Enzyme inhibitors; Fatty acid amide hydrolase; Screening library; Serine hydrolase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Serine Proteases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Serine Proteinase Inhibitors
  • Small Molecule Libraries
  • Serine Proteases