Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke |
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Authors: | Lucí a Viejo,Marcos Rubio-Alarcó n,Raquel L. Arribas,Manuel Moreno-Castro,Raquel Pé rez-Marí n,Marí a Braun-Cornejo,Martí n Estrada-Valencia,Cristó bal de los Rí os |
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Affiliation: | 1.Instituto-Fundación Teófilo Hernando and Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain; (L.V.); (M.R.-A.); (R.L.A.); (M.M.-C.); (R.P.-M.); (M.B.-C.);2.Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de La Princesa, 28006 Madrid, Spain |
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Abstract: | In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ 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 {"type":"entrez-protein","attrs":{"text":"CGP37157","term_id":"875406365","term_text":"CGP37157"}}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 Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments. |
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Keywords: | __tag_973584052" class=" tag_hotlink" href=" /protein/CGP37157" ref=" /protein/CGP37157" >{" type" :" entrez-protein" " attrs" :{" text" :" CGP37157" " term_id" :" 875406365" " term_text" :" CGP37157" }}CGP37157 benzothiazepines neuroprotection Ca2+ overload oxidative stress mitochondria |
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