National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
Eur J Med Chem. 2019 Apr 15;168:491-514. doi: 10.1016/j.ejmech.2019.02.021. Epub 2019 Feb 27.
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
他克林与色氨酸结合导致了新的杂二聚体家族的发展，作为具有治疗阿尔茨海默病潜力的多靶标药物。根据体外生物学特征，化合物 S-K1035 被发现是最有效的人乙酰胆碱酯酶 (hAChE) 和人丁酰胆碱酯酶 (hBChE) 抑制剂，对 hAChE 和 hBChE 的 IC 值分别为 6.3 和 9.1 nM。对于所有的他克林-色氨酸杂二聚体，在 hAChE 和 hBChE 上都表现出有利的抑制作用，这归因于这两个药效团之间最佳的 5 到 8 个碳原子间隔长度。S-K1035 还显示出良好的抑制 Aβ 自聚集的能力（在 50 μM 时为 58.6±5.1%），以及 hAChE 诱导的 Aβ 聚集的能力（在 100 μM 时为 48.3±6.3%）。TcAChE 与 S-K1035 复合物的 X 射线晶体学分析指出了杂交策略的应用和用两种 K1035 对映体与 hBChE 形成的复合物确定的结构的效用，可以解释 S-K1035 更高的抑制效力。其他体外评估预测了 S-K1035 穿过血脑屏障的能力，并对神经元型一氧化氮合酶具有适度的抑制作用。基于最初有希望的生化数据和与他克林相比更安全的体内毒性，S-K1035 被给予东莨菪碱处理的大鼠，能够剂量依赖性地逆转记忆障碍。
