Advances in prodrug design for Parkinson’s disease

ABSTRACT

Introduction: Parkinson’s Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension.

Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system.

Expert opinion: The prodrug strategy remains one of the most promising approaches to improve pharmaceutical, pharmacokinetic, and pharmacodynamic properties of hydrophilic compounds, such as anti-Parkinson drugs (DA and LD). Prodrugs developed in recent years have demonstrated good pharmacokinetic profiles, affording a sustained release of LD and reducing its plasma level fluctuations. The development of new prodrugs that may reach the BBB unaltered and with a good ADME (Absorption, Distribution, Metabolism, Elimination) profile and pharmacological efficacy represents an exciting challenge for medicinal chemists.

KEYWORDS:

• Dopamine
• L-Dopa
• Parkinson’s disease
• prodrug approach

Article highlights

• Despite recent advances in our understanding of the etiology of Parkinson’s Disease (PD), there is still the huge issue of delivering drugs across the blood brain barrier (BBB) to reach the central nervous system (CNS).

• The prodrug strategy has been one of the most successful approaches for delivering new molecular entities with improved physicochemical and pharmacological features.

• Although it causes motor complications through long-term use, Levodopa (LD) remains the ‘gold standard’ for the treatment of PD.

• There has been considerable development in the ability of prodrugs to improve BBB penetration exploiting one or more combined strategy: carrier-mediated transport in combination with endogenous ligands; lipophilic moieties to improve physicochemical features; combination of two distinct pharmacophores chemically linked together to improve the drug delivery properties.

• Recently, the combination of prodrugs with drug delivery systems have proved to be effective for brain targeting. The chemical and enzymatic protection operated by the carrier, joined with the capability of the prodrug to cross BBB, has allowed slow and sustained release, thus reducing the plasma fluctuation for better control of the disease.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This manuscript has not been funded.