Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Laboratory of Medicinal Chemistry (IQOG, CSIC), 3, Juan de la Cierva, 28006, Madrid, Spain.
Chem Rec. 2019 May;19(5):927-937. doi: 10.1002/tcr.201800155. Epub 2018 Nov 29.
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.
尽管他克林的临床应用受到严重肝毒性的阻碍，但他克林仍然是寻找治疗阿尔茨海默病的新有效药物的参考支架。在本报告中，我们总结了通过将苯环替换为 1,4-二氢吡啶、1,2,3,4-四氢嘧啶或吡啶酮核来开发和表征非肝毒性他克林嘧啶和相关他克林类似物的努力。这些努力成功地确定了许多具有有趣多功能特征的有前途的命中物。其中包括 4'-甲氧基他克林嘧啶 (S)-ITH122，能够靶向胆碱酯酶 (ChE)、β-淀粉样蛋白 (Aβ) 和钙通道，外消旋 3'-甲氧基他克林嘧啶 EB65F2，第一个完全平衡的微摩尔 ChE 和钙通道抑制剂，以及 GSK-3β（参与 tau 磷酸化的酶）抑制剂他克林嘧啶 (-)-SCR1693，能够降低 N2a 细胞中 Aβ的产生。
