Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca(2+) Overload for the Treatment of Neurodegenerative Diseases and Stroke

In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca(2+) levels. A dysregulation of the mitochondrial Ca(2+) buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na(+)/Ca(2+) exchanger (NCLX) is the principal efflux pathway of Ca(2+) to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca(2+) overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca(2+) regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.