用于治疗帕金森氏病的l-Dopa-Lazabemide前药的设计和评估。,Molecules

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用于治疗帕金森氏病的l-Dopa-Lazabemide前药的设计和评估。
Molecules ( IF 4.2 ) Pub Date : 2017-12-01 , DOI: 10.3390/molecules22122076
Monique Hoon ₁ , Jacobus P Petzer ₁ , Francois Viljoen ₂ , Anél Petzer ₁

Affiliation

l-Dopa是多巴胺的代谢前体，是缓解帕金森氏病晚期症状的首选治疗方法。然而，左旋多巴的口服生物利用度仅为约10％至30％，并且估计少于口服剂量的1％不变地到达大脑。l-Dopa的理化特性是其生物利用度差，半衰期短以及患者之间和患者体内血浆水平变化范围广的原因。提出了l-多巴-拉扎贝米特前药以克服与l-多巴吸收有关的问题。Lazabemide是单胺氧化酶（MAO）-B抑制剂，是一类化合物，可减慢帕金森氏病中多巴胺储存的消耗并提高由外源性左旋多巴产生的多巴胺水平。左旋多巴在羧酸盐处通过酰胺与拉沙贝米的伯胺基官能团连接，该策略有望保护左旋多巴免于周边脱羧并可能还增强前药的膜通透性。确定了前药的选定理化和生化特性，包括亲脂性（logD），溶解度，被动扩散渗透性，pKa，化学和代谢稳定性以及细胞毒性。尽管用前药对小鼠进行口服和腹腔注射治疗不会导致纹状体多巴胺水平升高，但与生理盐水，l-多巴和卡比多巴/ l-多巴治疗相比，3,4-二羟基苯基乙酸（DOPAC）的水平明显降低。根据结果，

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The Design and Evaluation of an l-Dopa-Lazabemide Prodrug for the Treatment of Parkinson's Disease.

l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson's disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa's physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa-lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO)-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson's disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD), solubility, passive diffusion permeability, pKa, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa-lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.

更新日期：2019-11-01

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