Notwithstanding the clinical use of tacrine was hampered by severe hepatotoxicity, tacrine still remains a reference scaffold in the search for new efficient drugs for Alzheimer's disease therapy. In this account we summarize the efforts toward the development and characterization of non-hepatotoxic tacripyrines and related tacrine analogues resulting from the substitution of the benzene ring by a 1,4-dihydropyridine, a 1,2,3,4-tetrahydropyrimidine or a pyridone nucleus. These efforts have successfully led to the identification of a number of promising hits endowed with interesting multifunctional profiles. These include the 4′-metoxytacripyrine (S)-ITH122, able to target cholinesterases (ChEs), beta-amyloid (Aβ) and Ca2+ channels, the racemic 3′-methoxytacripyrimidine EB65F2, the first fully balanced micromolar inhibitor of ChEs and Ca2+ channels, and tacripyrine (−)-SCR1693 a GSK-3β (enzyme involved in tau phosphorylation) inhibitor able to also lower Aβ production in N2a cells.

Bartolini, M., Marco-Contelles, J. (2019). Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines. THE CHEMICAL RECORD, 19(5), 927-937 [10.1002/tcr.201800155].

Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines

Bartolini, Manuela
;
2019

Abstract

Notwithstanding the clinical use of tacrine was hampered by severe hepatotoxicity, tacrine still remains a reference scaffold in the search for new efficient drugs for Alzheimer's disease therapy. In this account we summarize the efforts toward the development and characterization of non-hepatotoxic tacripyrines and related tacrine analogues resulting from the substitution of the benzene ring by a 1,4-dihydropyridine, a 1,2,3,4-tetrahydropyrimidine or a pyridone nucleus. These efforts have successfully led to the identification of a number of promising hits endowed with interesting multifunctional profiles. These include the 4′-metoxytacripyrine (S)-ITH122, able to target cholinesterases (ChEs), beta-amyloid (Aβ) and Ca2+ channels, the racemic 3′-methoxytacripyrimidine EB65F2, the first fully balanced micromolar inhibitor of ChEs and Ca2+ channels, and tacripyrine (−)-SCR1693 a GSK-3β (enzyme involved in tau phosphorylation) inhibitor able to also lower Aβ production in N2a cells.
2019
Bartolini, M., Marco-Contelles, J. (2019). Tacrines as Therapeutic Agents for Alzheimer's Disease. IV. The Tacripyrines and Related Annulated Tacrines. THE CHEMICAL RECORD, 19(5), 927-937 [10.1002/tcr.201800155].
Bartolini, Manuela*; Marco-Contelles, José
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/666764
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