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

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 Ca channels, the racemic 3′-methoxytacripyrimidine EB65F2, the first fully balanced micromolar inhibitor of ChEs and Ca channels, and tacripyrine (−)-SCR1693 a GSK-3β (enzyme involved in tau phosphorylation) inhibitor able to also lower Aβ production in N2a cells.The authors thank all the co-workers for their effort, commitment and contribution for the synthesis and biological evaluation of the tacrines discussed in this account, as well as the grants and support that have allowed to carry out the developments resumed here.Peer Reviewe