A Novel Parkinson’s Disease Drug Candidate with Potent Anti-neuroinflammatory Effects through the Src Signaling Pathway

Numerous drug treatments
are available for Parkinson’s disease
(PD), an age-related neurodegenerative disease, but most cause serious
side effects. Therefore, novel therapeutic strategies that halt disease
progression and allow for long-term administration are urgently needed.
Neuroinflammation critically contributes to the pathogenesis of PD.
Here, we report the discovery and optimization of phloroglucinol derivatives,
a novel class of anti-neuroinflammatory compounds. Structural modifications
of the hit compound 3-methyl-1-(2,4,6-trihydroxyphenyl)­butan-1-one
produced 43 derivatives, including a preclinical candidate (compound 21), that exhibited potent in vitro anti-neuroinflammatory
effects, good blood–brain barrier penetration, and desirable
safety margins in mice at a median lethal dose (LD50) >5000
mg/kg. Its in vivo efficacy was demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)- and MPTP/probenecid (prob)-induced subacute and chronic PD
models, respectively, and α-synuclein transgenic mice. Mechanistic
studies revealed neuroinflammation inhibition by targeting Src/phosphatase
and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling
might be promising. We highlighted the potential usefulness of phloroglucinol
derivatives in PD treatment.

帕金森病（Parkinson’s disease, PD）是一种年龄相关性神经退行性疾病，目前已有多种药物治疗方案，但多数药物会引发严重不良反应。因此，亟需能够阻断疾病进展且可长期给药的新型治疗策略。神经炎症在帕金森病的发病机制中发挥关键作用。本研究报道了一类新型抗神经炎症化合物——间苯三酚衍生物的发现与优化过程。对命中化合物3-甲基-1-(2,4,6-三羟基苯基)丁-1-酮进行结构修饰，共得到43种衍生物，其中包括临床前候选化合物21号，该化合物在体外展现出强效抗神经炎症活性，具备良好的血脑屏障穿透性，且在小鼠体内的半数致死量（LD50）＞5000 mg/kg，表现出优异的安全边际。其体内药效分别在1-甲基-4-苯基-1,2,3,6-四氢吡啶（1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP）及MPTP/丙磺舒（probenecid, prob）诱导的亚急性与慢性帕金森病模型，以及α-突触核蛋白转基因小鼠中得到验证。机制研究显示，通过靶向Src/张力蛋白同源且位于染色体10缺失的磷酸酶（PTEN）/Akt信号通路抑制神经炎症，是该类化合物极具潜力的作用机制。本研究凸显了间苯三酚衍生物在帕金森病治疗中的应用潜力。