title: Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na(+)/Ca(2+) exchanger.
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its potency and selectivity, we herein describe the synthesis of new CGP37157 analogs, where the benzene-fused ring has been replaced by a pyridine.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.
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Martínez-Sanz
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Lajarín-Cuesta
authors.affiliation: Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Moreno-Ortega
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Punzón
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain. Electronic address: maria.cano@uam.es.
authors.forename: María F
authors.initials: MF
authors.lastname: Cano-Abad
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029 Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006 Madrid, Spain. Electronic address: cristobal.delosrios@uam.es.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013841:Thiazepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000605974:7-chloro-5-(2-isopropylphenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one; D018696:Neuroprotective Agents; D011725:Pyridines; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D002118:Calcium
keywords: CGP37157; Mitochondria; Mitochondrial Na(+)/Ca(2+) exchanger; Neurodegeneration; Neuroprotection; Pyridothiazepines