1. Polycyclic maleimide-based derivatives as first dual modulators of neuronal calcium channels and GSK-3β for Alzheimer's disease treatment
- Author
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Federica Belluti, Angela Rampa, Cristóbal de los Ríos, Raquel L Arribas, Silvia Gobbi, Alessandra Bisi, Alessandra Feoli, Sabrina Castellano, Matteo Micucci, Roberta Budriesi, Bisi, Alessandra, Arribas, Raquel L., Micucci, Matteo, Budriesi, Roberta, Feoli, Alessandra, Castellano, Sabrina, Belluti, Federica, Gobbi, Silvia, de los Rios, Cristobal, and Rampa, Angela
- Subjects
Maleimide ,chemistry.chemical_element ,Pharmacology ,Calcium ,01 natural sciences ,Maleimides ,Ca(2+) channels ,03 medical and health sciences ,chemistry.chemical_compound ,N-Type ,Structure-Activity Relationship ,Calcium Channels, N-Type ,Polycyclic Compound ,GSK-3 ,Ca 2+ channels ,Alzheimer Disease ,Drug Discovery ,medicine ,Structure–activity relationship ,Humans ,Polycyclic Compounds ,GSK3B ,030304 developmental biology ,0303 health sciences ,Glycogen Synthase Kinase 3 beta ,Voltage-dependent calcium channel ,Alzheimer's disease ,Dual inhibitors ,GSK-3β ,Maleimide-based polycyclic scaffold ,010405 organic chemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,General Medicine ,medicine.disease ,0104 chemical sciences ,chemistry ,Dual inhibitor ,Calcium Channels ,Lead compound ,Human - Abstract
Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simultaneously modulate neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), validated targets to combat Alzheimer’ disease. Different structural modifications were performed on the polycyclic scaffold in order to investigate the structure-activity relationships and compound 10 emerged as a promising non-toxic lead compound, endowed with calcium modulating brain-addressed properties and significant GSK-3β inhibitory activity. Moreover, the easily affordable polycyclic core appears as a new appealing privileged structure in medicinal chemistry.
- Published
- 2019