Medicinal Chemistry Strategies to Combat Neurodegenerative Diseases

Novel and effective therapeutic agents for the treatment of neurodegenerative diseases are a major unmet medical need but also a key focus of medicinal chemistry research and drug discovery strategies. Despite their increasing prevalence, common neurodegenerative diseases, such as Alzheimer's and Parkinson's, still have no effective cure, making them a major health issue. Neurodegenerative disorders share several features and pathological mechanisms [1], such as the accumulation of intrinsically disordered proteins in the form of aggregates, the involvement of mitochondrial dysfunction, oxidative stress, and neuroin- flammation. These mechanisms have led to the development of therapeutic agents aimed at halting or slowing disease progres- sion rather than merely delaying the associated symptoms [2]. Despite considerable progress in understanding the pathogenesis of these diseases, the precise mechanisms that trigger neu- rodegeneration remain unclear. As a result, the search for novel, effective therapeutic strategies with disease-modifying out- comes is highly challenging. Driven by this increasing need for new therapeutic agents, we have come together to provide the mini-issue of 'Current Top- ics in Medicinal Chemistry.' In the three reviews of this mini-issue, the authors provide a critical analysis of both current and future approaches to the treatment of neurodegenerative diseases while also investigating potential novel targets and mechanisms underlying neuro- degeneration. It is well known that most neurodegenerative diseases have a multifactorial etiology. From this point of view, the develop- ment of multi-target directed ligands (MTDLs) [3] that simultaneously modulate multiple targets involved in the pathogenesis of neurodegenerative diseases appears to be a promising strategy. The review of Bayraktar [4] provides an in-depth look at new molecular target and their ligands, both single-targeted and MTDLs, for the treatment of Alzheimer's disease (AD). In particu- lar, the authors cover various biochemical pathways that have recently emerged as druggable targets, including cannabinoid receptors, matrix metalloproteinases, histone deacetylase, and various kinases, i.e., glycogen synthase kinase-3, mitogen- activated protein kinase, and c-Jun N-terminal kinase. In parallel, the authors provided an overview of single-targeted and MTDLs developed for each target class relevant to AD. In recent years, modulation of histaminergic transmission has been actively discussed as an attractive strategy for the treat- ment of neuroinflammatory disorders associated with cognitive decline. Lopes et al. [5] review the functions of histamine and its receptors in the central nervous system, highlighting the key role of the histamine H3 receptor (H3R) in neuroinflammation and cognitive impairment. The authors discuss single- and multi-targeted H3R modulators, their mechanism(s) of action, and pharmacological properties, focusing on the anti-neuroinflammatory potential for the treatment of neurodegenerative and cogni- tive disorders. The role of the sphingosine-1-phosphate (S1P) receptor in neurodegenerative diseases and the analysis of small molecule modulators were critically reviewed by Kar et al. [6]. The S1P pathway facilitates protective turnover in neuronal autophagy and is involved in immune cell trafficking. The authors discuss the development of small molecules targeting S1P, which has led to the approval of three S1P receptor modulators for multiple sclerosis. Additionally, the authors describes innovative drug candidates currently in preclinical or clinical development. We hope that the articles presented in this mini-issue of Current Topics in Medicinal Chemistry provide useful insights and stimulate further medicinal chemistry efforts in the field of neurodegenerative diseases.