Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2

Bioorg Med Chem Lett. 2011 May 1;21(9):2692-6. doi: 10.1016/j.bmcl.2010.12.037. Epub 2010 Dec 16.

Abstract

Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K(i) values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.

Publication types

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

MeSH terms

  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / antagonists & inhibitors*
  • GTP-Binding Proteins / metabolism
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Protein Glutamine gamma Glutamyltransferase 2
  • Structure-Activity Relationship
  • Transglutaminases / antagonists & inhibitors*
  • Transglutaminases / metabolism

Substances

  • Enzyme Inhibitors
  • Indoles
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins