Nam Min-Ho, Park Moosung, Park Hyeri, Kim Youngjae, Yoon Seulki, Sawant Vikram Shahaji, Choi Ji Won, Park Jong-Hyun, Park Ki Duk, Min Sun-Joon, Lee C Justin, Choo Hyunah
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
Department of Science in Korean Medicine, Graduate School, Kyung Hee University , Kyungheedaero 26, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
ACS Chem Neurosci. 2017 Jul 19;8(7):1519-1529. doi: 10.1021/acschemneuro.7b00050. Epub 2017 Mar 30.
To develop novel, selective, and reversible MAO-B inhibitors for safer treatment of Parkinson's disease, benzothiazole and benzoxazole derivatives with indole moiety were designed and synthesized. Most of the synthesized compounds showed inhibitory activities against MAO-B and selectivity over MAO-A. The most active compound was compound 5b, 6-fluoro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole with an IC value of 28 nM with no apparent effect on MAO-A activity at 10 μM. Based on the reversibility assay, compound 5b turned out to be fully reversible with over 95% of recovery of enzyme activity after washout of the compound. Compound 5b showed a reasonable stability in human liver microsomes and did not affect the activities of CYP isozymes, suggesting an absence of high-risk drug-drug interaction. In an in vivo MPTP-induced animal model of Parkinson's disease, oral administration of compound 5b showed neuroprotection of nigrostriatal dopaminergic neurons as revealed by tyrosine hydroxylase staining and prevention of MPTP-induced parkinsonism as revealed by motor behavioral assay of vertical grid test. In summary, the novel, reversible, and selective MAO-B inhibitor compound 5b was synthesized and characterized. We propose compound 5b as an effective therapeutic compound for relieving parkinsonism.
为开发新型、选择性和可逆的单胺氧化酶B（MAO-B）抑制剂以更安全地治疗帕金森病，设计并合成了带有吲哚部分的苯并噻唑和苯并恶唑衍生物。大多数合成化合物显示出对MAO-B的抑制活性以及对MAO-A的选择性。活性最高的化合物是化合物5b，即6-氟-2-(1-甲基-1H-吲哚-5-基)苯并[d]噻唑，其IC值为28 nM，在10 μM时对MAO-A活性无明显影响。基于可逆性测定，化合物5b被证明是完全可逆的，在洗去该化合物后酶活性恢复超过95%。化合物5b在人肝微粒体中显示出合理的稳定性，并且不影响细胞色素P450（CYP）同工酶的活性，表明不存在高风险的药物相互作用。在体内1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病动物模型中，口服化合物5b显示出对黑质纹状体多巴胺能神经元的神经保护作用，酪氨酸羟化酶染色显示了这一点，并且通过垂直网格试验的运动行为测定表明预防了MPTP诱导的帕金森症。总之，合成并表征了新型、可逆且选择性的MAO-B抑制剂化合物5b。我们提出化合物5b作为缓解帕金森症的有效治疗化合物。
