Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na(+)/Ca(2+) exchanger

European Journal of Medicinal Chemistry
Francisco J Martínez-SanzCristóbal de Los Ríos

Abstract

The mitochondrial Na(+)/Ca(2+) exchanger plays an important role in the control of cytosolic Ca(2+) cycling in excitable cells, essential for the regulation of a plethora of Ca(2+)-dependent physio-pathological events, such as apoptosis in the presence of a Ca(2+) overload. There are very few pharmacological tools available to study both physiological and pathological implications of the mitochondrial Na(+)/Ca(2+) exchanger, where the benzothiazepine CGP37157 is the best-known ligand, used since the 1980s. However, it is not an efficient blocker and lacks of selectivity, as also blocks several other cellular Ca(2+) transporters. Moreover, CGP37157 is a very lipophilic drug, showing very poor water solubility, what has hindered its therapeutic use. Attempting to improve its pharmacokinetic profile as well as its potency and selectivity, we herein describe the synthesis of new CGP37157 analogs, where the benzene-fused ring has been replaced by a pyridine. On top of a better water solubility and lower log P value, some of these new pyridothiazepine derivatives also presented a higher capacity to regulate the mitochondrial Ca(2+) clearance, while keeping the neuroprotective properties presented in the head compound CGP37157.

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Citations

Aug 22, 2017·Pflügers Archiv : European journal of physiology·Cristobal de Los RiosManuela G López
Feb 2, 2019·Frontiers in Aging Neuroscience·Paloma García-CasasJavier Alvarez
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lucía ViejoCristóbal de Los Ríos

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