Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease.
Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease.
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DOI：
10.3390/molecules23010040
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发表时间：
2017-12-25
期刊：
影响因子：
--
通讯作者：
Karaman R
中科院分区：
文献类型：
--
作者：
Haddad F;Sawalha M;Khawaja Y;Najjar A;Karaman R
背景：帕金森病是一种侵袭性和进行性的神经退行性疾病，它消耗中枢神经系统中的多巴胺（DA）。多巴胺替代疗法，主要是通过实际的多巴胺及其原始前药左旋多巴（LD），面临着许多挑战，如血脑屏障渗透性差，随着时间的推移对治疗的反应下降。研究方法：本文所述的前药是通过化学手段设计和制备的酯、酰胺、二聚酰胺、载体介导的、肽转运介导的、环状的、化学递送系统和酶模型前药，并且在动物中研究了它们的生物利用度。结果：开发了一种很有前途的酯型前药鼻腔给药系统。LD甲酯目前处于III期临床试验阶段。合成了一系列酰胺类前药，其稳定性优于酯类前药。酰胺和二聚酰胺前药均提供增强的血脑屏障（BBB）渗透和更好的药代动力学。将LD连接到糖上已被用于利用葡萄糖转运机制进入大脑。结论：目前，还没有DA前体药物进入医药市场，然而，利用DA前体药物治疗PD的前景似乎是光明的。例如，LD酯前药已经证明了LD的充分鼻内递送，从而使得治疗剂能够吸收到脑中。DA前药的大多数酰胺、环状、肽基或化学递送系统表现出增强的药代动力学性质。
Background: Parkinson’s disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods: The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. Results: A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. Conclusions: Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties.
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