Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors
Open Access
- 30 November 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (23), 14761-14779
- https://doi.org/10.1021/acs.jmedchem.0c01305
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.Keywords
Funding Information
- Fondazione Telethon (GGP19110)
- Associazione Italiana per la Ricerca sul Cancro (22568)
This publication has 47 references indexed in Scilit:
- Ca 2+ release-activated Ca 2+ channel blockade as a potential tool in antipancreatitis therapyProceedings of the National Academy of Sciences of the United States of America, 2013
- Novel pyrazole compounds for pharmacological discrimination between receptor‐operated and store‐operated Ca2+ entry pathwaysBritish Journal of Pharmacology, 2012
- Nanomolar potency and selectivity of a Ca2+release-activated Ca2+channel inhibitor against store-operated Ca2+entry and migration of vascular smooth muscle cellsBritish Journal of Pharmacology, 2011
- Genetic and Pharmacologic Inhibition of the Ca2+ Influx Channel TRPC3 Protects Secretory Epithelia From Ca2+-Dependent ToxicityGastroenterology, 2011
- InsP3 receptors and Orai channels in pancreatic acinar cells: co-localization and its consequencesBiochemical Journal, 2011
- The Physiological Function of Store-operated Calcium EntryNeurochemical Research, 2011
- Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compoundProceedings of the National Academy of Sciences of the United States of America, 2009
- Store-Operated Calcium ChannelsPhysiological Reviews, 2005
- Depletion of intracellular calcium stores activates a calcium current in mast cellsNature, 1992
- A model for receptor-regulated calcium entryCell Calcium, 1986