Pont Caterina, Sampietro Anna, Pérez-Areales F Javier, Cristiano Nunzia, Albalat Agustí, Pérez Belén, Bartolini Manuela, De Simone Angela, Andrisano Vincenza, Barenys Marta, Teixidó Elisabet, Sabaté Raimon, Loza M Isabel, Brea José, Muñoz-Torrero Diego
Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
Institute of Biomedicine of the University of Barcelona (IBUB), E-08028 Barcelona, Spain.
Pharmaceutics. 2024 Jul 25;16(8):982. doi: 10.3390/pharmaceutics16080982.
Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein-huprine hybrid lead by hydroxy group removal-ring contraction-ring opening-ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification.
多靶点化合物已成为应对复杂多因素疾病（如阿尔茨海默病（AD））的有前景的候选药物。大多数多靶点化合物是通过连接链将两个药效团连接起来设计而成（连接型杂合物），这会产生相当大的分子，特别适用于作用于具有大结合腔的靶点，但代价是其物理化学/药代动力学性质欠佳。在保留关键药效团基序的同时去除多余结构元素以减小分子大小，可能是实现多靶点作用以及良好物理化学/药代动力学性质的折衷解决方案。在此，我们报告了大黄酸 - 石杉碱杂交先导物中二羟基蒽醌部分通过羟基去除 - 环收缩 - 环开环 - 环去除进行的逐步结构简化，这导致了新的类似物，它们在多个AD靶点上保留或超过了先导物的效力，同时表现出更有利的药物代谢和药代动力学（DMPK）性质及安全性。特别是，最简化的苯乙酮类似物对人乙酰胆碱酯酶和丁酰胆碱酯酶具有双重纳摩尔抑制作用（IC分别为6 nM和13 nM），对人β - 分泌酶1（BACE - 1）具有中等强度抑制作用（在15 μM时抑制率为48%），对Aβ42和tau聚集具有抑制作用（在10 μM时分别为73%和68%），具有良好的体外脑渗透性、更高的水溶性（18 μM）和血浆稳定性（在人/小鼠/大鼠血浆中孵育6小时后分别剩余100/96/86%），并且在模型生物（斑马鱼胚胎；LC >> 100 μM）中的急性毒性低于初始先导物，从而证实了通过结构简化成功实现了先导物优化。
