Department of Bioorganic & Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine.
Molecules. 2017 Dec 25;23(1):40. doi: 10.3390/molecules23010040.
: 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. : 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. 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. : 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.
帕金森病是一种侵袭性和进行性神经退行性疾病，会导致中枢神经系统中的多巴胺（DA）耗竭。多巴胺替代疗法主要通过实际的多巴胺及其前体左旋多巴（LD）来实现，但面临许多挑战，如血脑屏障通透性差和随着时间的推移治疗反应下降。本文所述的前体药物是通过化学手段设计和制造的酯、酰胺、二酰胺、载体介导、肽转运介导、环状、化学传递系统和酶模型前体药物，研究了它们在动物中的生物利用度。已经开发出一种有前途的用于鼻内给药的酯前体药物。LD 甲酯目前正在进行 III 期临床试验。合成了一系列稳定性优于酯前体药物的酰胺前体药物。酰胺和二酰胺前体药物都提供了增强的血脑屏障（BBB）穿透性和更好的药代动力学特性。将 LD 连接到糖上已被用于利用葡萄糖转运机制将药物输送到大脑。到目前为止，还没有任何 DA 前体药物进入医药市场，但利用前体药物治疗 PD 的前景似乎很光明。例如，LD 酯前体药物已经证明了 LD 的鼻腔内输送足够，从而使治疗剂能够被吸收到大脑中。大多数 DA 前体药物的酰胺、环状、肽或化学传递系统都表现出增强的药代动力学特性。
