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.
Beatrice Riva  1  2 ,  Alessia Griglio  1 ,  Marta Serafini  1 ,  Celia Cordero-Sanchez  1 ,  Silvio Aprile  1 ,  Rosanna Di Paola  3 ,  Enrico Gugliandolo  3 ,  Dalia Alansary  4 ,  Isabella Biocotino  1 ,  Dmitry Lim  1 ,  Giorgio Grosa  1 ,  Ubaldina Galli  1 ,  Barbara Niemeyer  4 ,  Giovanni Sorba  1 ,  Pier Luigi Canonico  1 ,  Salvatore Cuzzocrea  3 ,  Armando A Genazzani  1 ,  Tracey Pirali  1  2
Affiliations
  • 1. Department of Pharmaceutical Sciences , Università del Piemonte Orientale , Novara 28100 , Italy.
  • 2. ChemICare Srl , Enne3 , Novara 28100 , Italy.
  • 3. Department of Chemical, Biological, Pharmaceutical, and Enviromental Sciences , Università di Messina , Messina 98166 , Italy.
  • 4. Department of Molecular Biophysics , Saarland University CIPMM , Homburg 66421 , Germany.
PMID: 30347159 DOI: 10.1021/acs.jmedchem.8b01512
Abstract

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.

Products