jm8b01512_si_001.pdf (1.38 MB)

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

Download (1.38 MB)
journal contribution
posted on 22.10.2018, 00:00 by Beatrice Riva, Alessia Griglio, Marta Serafini, Celia Cordero-Sanchez, Silvio Aprile, Rosanna Di Paola, Enrico Gugliandolo, Dalia Alansary, Isabella Biocotino, Dmitry Lim, Giorgio Grosa, Ubaldina Galli, Barbara Niemeyer, Giovanni Sorba, Pier Luigi Canonico, Salvatore Cuzzocrea, Armando A. Genazzani, Tracey Pirali
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.