Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis

J Med Chem. 2018 Nov 8;61(21):9756-9783. doi: 10.1021/acs.jmedchem.8b01512. Epub 2018 Oct 30.


In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Biological Transport / drug effects
  • Calcium / metabolism*
  • Drug Design*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Pancreatitis / drug therapy*
  • Triazoles / chemistry*
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use


  • Triazoles
  • Calcium