858 research outputs found
Malattia di Alzheimer, nuove strategie di Drug Discovery
No full textAlzheimer’s disease (AD) is a complex neurodegenerative disorder resulting from multiple molecular abnormalities, and not from a single target/gene defect. This may explain why the currently available drugs and mostly of the candidates in the pipeline, developed according to the classic drug discovery paradigm of “one-molecule-one-target”, have turned out to be palliative or have failed in achieving any curative effect. This has led to a new paradigm in medicinal chemistry, the “multi-target-directed ligand” design strategy, which has already been exploited at both academic and industrial levels [1]. Multi-target-directed ligands (MTDLs) are small molecules rationally designed to simultaneously modulate multiple targets involved in the neurotoxic cascade. Thus, they should be well-suited to addressing the multifactorial etiopathogenesis of AD.
In parallel, there has been a shift in interest from a target-centric approach, which attempts to limit drug action to the level of individual genes and single proteins, to a system approach, which is better suited to the complexity of the disease. The early signs of this paradigm shift are now being registered, as AD is increasingly studied at multiple levels, and new scientific advances are providing insights into the functioning of interacting biomolecules within cells or organisms [2]. In particular, since a significant number of therapeutic targets reside inside cells and intracellular organelles, subcellular targeting strategies for drug design and delivery now represent a considerable drug discovery challenge [3].
Herein, we present our research efforts that, moving on from classic drug discovery approaches, have produced innovative molecular probes and promising drug candidates for AD treatment.
[1] A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre. J. Med. Chem. 2008, 51, 347-72.
[2] M. L. Bolognesi, R. Matera, A. Minarini, M. Rosini, V. Tumiatti, C. Melchiorre. Curr. Opin. Chem. Biol. 2009, 13, 303-8.
[3] L. Rajendran, H. J. Knölker, K. Simons. Nature Rev. Drug Discov. 2010, 9, 29-42
Farmaci per le malattie neurodegenerative
No full textLe malattie neurodegenerative costituiscono un gruppo eterogeneo di patologie che condividono un progressivo e irreversibile deterioramento del sistema nervoso. Si tratta di forme invalidanti, per lo sviluppo delle quali l’età avanzata rappresenta in genere il fattore di rischio maggiore. La malattia di Alzheimer, la malattia di Parkinson, la corea di Huntington e la sclerosi laterale amiotrofica sono tra le più diffuse. Allo stato attuale, le
uniche terapie disponibili sono sintomatiche ed esercitano un’azione meramente palliativa. Data la complessità di tali patologie, l’azione simultanea su più target di rilievo offre prospettive di migliori risultati terapeutici. A oggi, questa strategia trova applicazione clinica nella somministrazione combinata di farmaci
Riduzione Diastereoselettiva di alfa-Chetoesteri Derivati da Monobenzileteri dell’(R,R)-1,2-Difeniletan-1,2-diolo
No full textMonobenzileteri di (R,R)-1,2-Difenil-1,2-etandiolo come Potenziale Alternativa agli Ausiliari Chirali di tipo Cicloesilico: Riduzione Diastereoselettiva di alfa-Chetoesteri
No full textMonobenzylether of (R,R)-1,2-Diphenylethane-1,2-diol as Chiral Auxiliary in the Diastereoselective Reduction of a-Ketoesters
No full textThe α-ketoester 4a, prepared in 3 steps from (R,R)-1,2-diphenylethane- 1,2-diol can be reduced with several agents providing the corresponding α- hydroxyester 5 with diastereoselectivities up to 56%. This selectivity has been interpreted as due to carbonyl face-shielding by the stacked OCH2Ph moiety of 4a
Multitargeted design strategy for Alzheimer’s drugs: focus on anticholinesterase and antiamyloid activities
No full textAlzheimer’s disease (AD) is a complex multifactorial syndrome where genetic predisposition interacts with environmental factors. Currently, AD pharmacotherapy relies on acethylcholinesterase inhibitors (AChEIs), valuable in restoring the cholinergic dysfunction, and memantine, a non competitive NMDA receptor antagonist that limits glutamate excitotoxicity. Despite considerable scientific progress, current drugs, developed according to the classic drug discovery paradigm of “one-molecule-one target”, offer only limited and transient benefits to patients. Therefore, in response to the molecular complexity of AD, a new strategy has recently emerged, that is the development of single chemical entities able to modulate multiple pathogenetic factors involved in the neurodegenerative process. This has led to a new paradigm in medicinal chemistry, the “multi-target directed ligands” (MTDLs) design strategy, that has already been exploited at both academic and industrial levels [1].
As in any drug discovery process, selecting optimal targets is a critical step and an important criterion for determining the success of new MTDLs. In our first attempts to design MTDLs, we focused on acetylcholinesterase (AChE), since the report that it plays other roles in addition to its ‘classical’ function in terminating cholinergic impulse, renewed the interest in AChEIs drug discovery [2].
In the years, the amyloid hypothesis has dominated the field of AD research and has provided the intellectual framework for therapeutic intervention. However, the view that Aβ is one of the factors, and not the only factor underlying AD pathogenesis, is more consistent with current knowledge, and may account for the failure of purely anti-amyloid strategies [3].
These considerations prompted us to develop new MTDLs possessing AChE inhibitory activity together with the ability to modulate Aβ secretion and aggregation.
Starting from lead candidates memoquin and bis(7)-tacrine, for which a multimodal profile has been previously disclosed, two novel series of dual anticholinesterase and antiamyloid compounds have been designed and synthesized.
The biological profile of the new derivatives against human cholinesterases (acetyl- and butyrylcholinesterase), Aβ aggregation promoted by AChE, self induced Aβ aggregation and BACE-1 was investigated.
[1] Cavalli et al. (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51, 347-372.
[2] Galdeano et al. (2010) Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-Alzheimer agents. Curr. Pharm. Des. 16, 2818-2836.
[3] Pimplikar (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int. J. Biochem. Cell. Biol. 41, 1261-1268
Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways
No full textFyn kinase is a member of the Src non-receptor tyrosine kinase family. Fyn is involved in multiple signaling pathways extending from cell proliferation and differentiation to cell adhesion and cell motility, and it has been found to be overexpressed in various types of cancers. In the central nervous system, Fyn exerts several different functions such as axon-glial signal transduction, oligodendrocyte maturation and myelination, and it is implicated in neuroinflammatory processes. Based on these premises, Fyn emerges as an attractive target in cancer and neurodegenerative disease therapy, particularly Alzheimer disease (AD), based on its activation by Aβ via cellular prion protein and its interaction with tau protein. However, Fyn is also a challenging target since the Fyn inhibitors discovered so far, due to the relevant homology of Fyn with other kinases, suffer from off-target effects. This review covers the efforts performed in the last decade to identify and optimize small molecules that effectively inhibit Fyn, both in enzymatic and in cell assays, including drug repositioning practices, as an opportunity of therapeutic intervention in neurodegeneration
Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea
No full textThe immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of Echinacea spp. and Curcuma longa, focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies
Oxidative stress in Alzheimer’s disease: are we connecting the dots?
No full textRedox impairment is a prominent feature of Alzheimer’s disease (AD). It has led to the “oxidative stress hypothesis”, which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially
critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field.
Future directions of antioxidant research are also presented
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