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Molecules 2017, 22(12), 2076; doi:10.3390/molecules22122076

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

1
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
2
Pharmacology, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa
*
Author to whom correspondence should be addressed.
Received: 5 October 2017 / Revised: 22 November 2017 / Accepted: 23 November 2017 / Published: 27 November 2017
(This article belongs to the Section Medicinal Chemistry)
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Abstract

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. View Full-Text
Keywords: lazabemide; l-dopa; prodrug; monoamine oxidase; MAO; inhibition; physicochemical properties lazabemide; l-dopa; prodrug; monoamine oxidase; MAO; inhibition; physicochemical properties
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Hoon, M.; Petzer, J.P.; Viljoen, F.; Petzer, A. The Design and Evaluation of an l-Dopa–Lazabemide Prodrug for the Treatment of Parkinson’s Disease. Molecules 2017, 22, 2076.

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