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

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.

Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells

“…Several chemical inhibitors [ 23 , 24 , 25 , 26 , 27 ] as well as potentiators of SOCE [ 28 , 29 , 30 ] have been reported. However, 2-aminoethyl diphenylborinate (2-APB, Figure 1 ) remains the best characterized compound used to modulate store-operated CRAC channels, despite of its effects on other known targets [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors

“…9 and 18 were tested for activity on SOCE in HEK cells, a human embryonic kidney (HEK) cell line, by fluorescence microscopy, as described elsewhere. 16 After 600 s, Ca 2+ was added and intracellular levels were measured. Compared to Synta66 , which exhibits an inhibition of 90.8 ± 1.7%, compound 18 inhibited SOCE to a smaller extent (26.2 ± 6.5%), whereas 9 showed a percentage of −4.9 ± 21.3, indicating that the molecule slightly increased Ca 2+ entry compared to control ( Table 1 ).…”

“…Among the several medicinal chemistry campaigns aimed at developing SOCE inhibitors, 15 in 2018 our research group described a class of SOCE modulators, named pyrtriazoles, 16 that were designed based on a known chemical probe for SOCE, Pyr6. 17 Among the reported compounds, a promising candidate ( 3 , Figure 1 ) able to significantly ameliorate cerulein-induced AP in rodents without signs of toxicity was identified.…”

Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors

“…In 2014, imidazothiazole compounds were reported by Tojo et al as potent IDO1 inhibitors, with the reference compound 1 (Figure 1) displaying an IC 50 value of 1.9 µM (rhIDO1) [10]. Taking advantage of our extensive experience both in multicomponent reactions [11,12] and click chemistry approach [13], as well as their exploitation in drug discovery [14,15,16,17], we decided to synthesize in parallel two series of imidazothiazole analogues.…”