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New 5-unsubstituted dihydropyridines with improved CaV1.3 selectivity as potential neuroprotective agents against ischemic injury.

Abstract：

:C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipine. Furthermore, they were able to protect neuroblastoma cells against Ca(2+) overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca(2+) dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency toward the cardiovascular channel subtype makes them safer by reducing their probable side effects, in comparison to classical 1,4-dihydropyridines. Some compounds afforded good protective profile in a postincubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window of opportunity of great interest for patient recovery after a brain ischemic episode. Good activities were also found in acute ischemia/reperfusion models of oxygen and glucose deprivation.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Tenti G,Parada E,León R,Egea J,Martínez-Revelles S,Briones AM,Sridharan V,López MG,Ramos MT,Menéndez JC

doi

10.1021/jm500263v

subject

Has Abstract

pub_date

2014-05-22 00:00:00

pages

4313-23

issue

10

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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