1,720,991 research outputs found
Medicinal Chemistry Strategies to Combat Neurodegenerative Diseases
No full textNovel 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
Polypharmacology approaches for brain disorders aimed to enhance brain permeability and circadian clock targeting
No full textCircadian rhythm disruption (CRD) is a common feature of several brain disorders. The restoration of circadian clock function and the development of circadian-based therapies may have significant therapeutic implications for brain diseases that extend beyond sleep disorders. However, several challenges persist due to the complexity of circadian interactions with multiple cellular pathways underlying CRD in brain diseases, together with the CNS compartmentalization, including the presence of the blood–brain barrier (BBB). Against these drawbacks, polypharmacology is a promising strategy to potentially provide greater efficacy by targeting multiple components of the CRD network through drug combinations or multi-target-directed ligands. Polypharmacology also offers innovative approaches to brain drug delivery by enhancing BBB penetration of CNS-directed drugs using combinations, co-drugs, and targeted prodrugs. Herein, we review polypharmacological strategies to improve BBB permeability of CNS agents and suggest the exploitation of polypharmacology as a promising new avenue for circadian clock modulation in the treatment of brain disorders
New Therapeutic Modalities in Prion Diseases
No full textPrion diseases are fatal neurodegenerative disorders for which no effective therapies exist. Despite decades of drug discovery efforts, progress in developing disease-modifying treatments has been slow. However, recent advances have introduced novel therapeutic modalities targeting key aspects of prion pathology, including prion protein biogenesis, aggregation, and degradation. Advancements in diagnostic tools and highly sensitive prion detection methods are also playing a crucial role in enabling early and accurate diagnosis, which is essential for the timely application of emerging therapeutics. This chapter explores novel therapeutic modalities for prion diseases, focusing on small-molecule theranostics and compounds promoting prion protein degradation, RNA-based therapeutics, and gene therapy approaches. We critically assess the advantages and limitations of these therapeutic strategies, considering their development, efficacy, and translational potential. By leveraging these innovative modalities, the therapeutic toolbox for prion diseases is expanding, offering hope for the development of effective treatments
Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?
Full text linkClick chemistry is universally recognized as a powerful strategy for the fast and precise assembly of diverse building blocks. Targeted Protein Degradation (TPD) is a new therapeutic modality based on heterobifunctional small-molecule degraders that provides new opportunities to medicinal chemists dealing with undruggable targets and incurable diseases. Here, we highlight how very recently the TPD field and that of click chemistry have merged, opening up the possibility for fine-tuning the properties of a degrader, chemically assembled through a "click" synthesis. By reviewing concrete examples, we want to provide the reader with the insight that the application of click and bioorthogonal chemistry in the TDP field may be a winning combination."Click chemistry" and targeted protein degradation - two flourishing trends in medicinal chemistry. May they be a winning combination? In this review, we provide the reader with selected examples offered by the combination of these two approaches trying to find a response to this question.imag
Harnessing the 12 Green Chemistry Principles for Sustainable Antiparasitic Drugs: Toward the One Health Approach
Full text linkAntiparasitic drug development stands as a critical endeavor in combating infectious diseases which, by affecting the well-being of humans, animals, and the environment, pose significant global health challenges. In a scenario where conventional pharmacological interventions have proven inadequate, the One Health approach, which emphasizes interdisciplinary collaboration and holistic solutions, emerges as a vital strategy. By advocating for the integration of One Health principles into the R&D pharmaceutical pipeline, this Perspective promotes green chemistry methodologies to foster the development of environmentally friendly antiparasitic drugs for both human and animal health. Moreover, it highlights the urgent need to address vector-borne parasitic diseases (VBPDs) within the context of One Health-driven sustainable development, underscoring the pivotal role of medicinal chemists in driving transformative change. Aligned with the Sustainable Development Goals (SDGs) and the European Green Deal, this Perspective explores the application of the 12 Principles of Green Chemistry as a systematic framework to guide drug discovery and production efforts in the context of VBPD. Through interdisciplinary collaboration and a constant commitment to sustainability, the field can overcome the challenges posed by VBPD while promoting global and environmental responsibility. Serving as a call to action, scientists are urged to integrate One Health concepts and green chemistry principles into routine drug development practices, thereby paving the way for a more sustainable R&D pharmaceutical pipeline for antiparasitic drugs
Medicinal Chemistry: A Key Driver in Achieving the Global Sustainable Development Goals
No full textIn 2015, the United Nations officially launched the Sustainable Development Goals (SDGs) as “the blueprint to achieve a better and more sustainable future for all. They address the global challenges we face, including those related to poverty, inequality, climate change, environmental degradation, peace and justice. The 17 Goals are all interconnected, in order to leave no one behind, it is important that we achieve them all by 2030”. Here, we have embedded medicinal chemistry as a key player to achieve SDGs. We firmly believe that medicinal chemistry can and must contribute to a sustainable future and a better world with an improved quality of life for all. We have taken a critical look at each of the SDGs, dividing them into Priority and Foundational, and analyzed how medicinal chemistry has an impact on each of them. Although much has been done, we are determined to make progress in this area
Overcoming the Challenges of Multi‐Target‐Directed Ligands for Alzheimer's Disease
No full textThe concept of multi‐target‐directed ligands has been quite successful within the drug discovery community, due to its potential to better address the multifactorial nature of complex diseases. However, translating one of these ligands into new drugs has turned out generally complicated, even more for the Alzheimer's disease field. Here we describe some of the faced challenges, with specific focus on a number of “culprits” including target selection, pharmacokinetics, and the use of appropriate disease models. We further provide medicinal chemistry case studies that have addressed one of them to more critically adjust for challenges on our way to therapeutics
Tackling Neuroinflammation in Cognitive Disorders with Single-targeted and Multi-targeted Histamine H3 Receptor Modulators
No full textNeuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here
Neuroregeneration versus neurodegeneration: Toward a paradigm shift in Alzheimer's disease drug discovery
No full textAlzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease
From Companion Diagnostics to Theranostics:A New Avenue for Alzheimer's Disease?
Full text linkThe recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted.</p
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