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

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.