Abstract
Store-operated calcium entry (SOCE) is important in the maintenance of calcium homeostasis and alterations in this mechanism are responsible for several pathological conditions, including acute pancreatitis. Since the discovery of SOCE, many inhibitors have been identified and extensively used as chemical probes to better elucidate the role played by this cellular mechanism. Nevertheless, only a few have demonstrated drug-like properties so far. Here, we report a class of biphenyl triazoles among which stands out a lead compound, 34, that is endowed with an inhibitory activity at nanomolar concentrations, suitable pharmacokinetic properties, and in vivo efficacy in a mouse model of acute pancreatitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biphenyl Compounds / chemical synthesis
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Biphenyl Compounds / metabolism
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Biphenyl Compounds / therapeutic use*
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Calcium / metabolism*
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Calcium Channel Blockers / chemical synthesis
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Calcium Channel Blockers / metabolism
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Calcium Channel Blockers / therapeutic use*
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Cell Line
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Dihydroorotate Dehydrogenase
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Drug Discovery
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Drug Stability
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use
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Humans
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Male
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Mice, Inbred C57BL
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Molecular Structure
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Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
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Pancreatitis / drug therapy*
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Pancreatitis / metabolism
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Pancreatitis / pathology
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Solubility
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / metabolism
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Triazoles / therapeutic use*
Substances
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Biphenyl Compounds
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Calcium Channel Blockers
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Dihydroorotate Dehydrogenase
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Enzyme Inhibitors
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Triazoles
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Oxidoreductases Acting on CH-CH Group Donors
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Calcium