Current Small Molecule–Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics

Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) are highly complex and possess multifactorial aetiologies. Further, the burden of NDDs has increased in recent years. However, very few Food And Drug Administration (FDA) approved drugs are available to slow down the progression of NDDs due to various challenges faced by medicinal chemists and neuroscientists, which include poor pharmacokinetics (PK), inability to cross the blood–brain barrier (BBB), and targeting the single cause of the disease. In this review, we have highlighted the medicinal chemistry approaches taken by medicinal chemists and neuroscientists in recent years to improve the pharmacokinetics (PK), stability, and pharmacodynamics of the existing FDA-approved drugs. Further, we have highlighted a few approaches and strategies taken by the medicinal chemist to slow down the progression of neurodegeneration. This review will also delineate the importance of collaboration in the field of drug discovery. Understanding the spectrum of overlapping biological pathways, drug metabolism and pharmacokinetics (DMPK) could give an edge to combat the complex pathogenesis of neurodegenerative diseases like ALS, AD, and PD.

Abstract

Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule–based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood–brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule–based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web–based computational tools. To increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal chemists in the pre–clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.

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