Parkinson's disease (PD) is a common neurodegenerative disease among the elderly. Currently, monoamine oxidase B (MAO-B) inhibitors are extensively used for PD in clinics. In this work, a series of novel chiral fluorinated pyrrolidine derivatives were designed and synthesized. In vitro biological evaluations revealed that compound D5 was the most potent, selective MAO-B inhibitor (IC₅₀ = 0.019 μM, MAO-A/MAO-B selectivity index = 2440), which was 10-fold than that of miracle drug safinamide (IC₅₀ = 0.163 μM, MAO-A/MAO-B selectivity index = 172). It was verified that the enhanced hydrophobic interaction of D5 improved the activity against MAO-B in molecular docking study. Besides, D5 exhibited excellent metabolic properties and pharmacokinetic profiles in monkeys and rats. Moreover, D5 displayed more efficacious than safinamide in vivo models. In the MPTP-induced PD mouse model, D5 significantly alleviated DA deficits and increased the effect of levodopa on dopamine concentration in the striatum. Meanwhile, D5 produced a prominent reduction in tremulous jaw movements induced by galantamine. Accordingly, we present D5 as a novel, highly potent, and selective MAO-B inhibitor for PD therapy.

帕金森病（PD）是老年人常见的神经退行性疾病。目前，单胺氧化酶B（MAO-B）抑制剂在临床上广泛用于PD。在这项工作中，设计并合成了一系列新型手性氟化吡咯烷衍生物。体外生物学评价显示，化合物D5是最有效的选择性 MAO-B 抑制剂（IC ₅₀  = 0.019 μM，MAO-A/MAO-B 选择性指数 = 2440），是神药沙芬酰胺的 10 倍。 IC ₅₀  = 0.163 μM，MAO-A/MAO-B 选择性指数 = 172)。在分子对接研究中证实，D5增强的疏水相互作用提高了对MAO-B的活性。此外，D5在猴子和大鼠中表现出优异的代谢特性和药代动力学特征。此外，在体内模型中， D5比沙芬酰胺更有效。在 MPTP 诱导的 PD 小鼠模型中，D5显着减轻了 DA 缺陷并增加了左旋多巴对纹状体中多巴胺浓度的影响。同时，D5显着减少了由加兰他敏引起的下颌颤动。因此，我们将D5作为一种新型的、高效的、选择性的 MAO-B 抑制剂用于 PD 治疗。