ethyl-1-(4-(2-3-3-trichloroacrylamido)phenyl)-5-(trifluoromethyl)-1h-pyrazole-4-carboxylate and Acute-Disease

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.

Topics: Acute Disease; Animals; Biological Transport; Calcium; Drug Design; Endoplasmic Reticulum; HEK293 Cells; Humans; Mice; Pancreatitis; Triazoles