Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure−activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases

Microtubule-stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as candidate therapeutics for neurodegenerative disease: Matched molecular pair analyses and computational studies reveal new structure-activity insights

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer’s disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure–activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity

A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials

Synthèse et relation structure-propriétés photophysiques de nouveaux fluorophores diaziniques obtenus par réactions de couplage croisé et "Click Chemistry"

ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Une seule dose psychotomimétique de kétamine diminue les fuseaux thalamocorticaux et les oscillations delta chez le rat sédaté.

International audienceBACKGROUND: In patients with psychotic disorders, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the spindle deficit observed in schizophrenia.METHODS: An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine in the sensorimotor and associative/cognitive thalamocortical (TC) systems. RESULTS: Under the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations.CONCLUSION: The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.CONTEXTE: Chez des patients souffrant de troubles psychotiques, la densité des fuseaux de sommeil est diminuée, ce qui soutient l'hypothèse que le thalamus et la neurotransmission glutamatergique jouent un rôle étio-physiopathologique crucial, dont les mécanismes sous-jacents restent inconnus. Nous avons émis l'hypothèse selon laquelle un hypofonctionnement des récepteurs NMDA est impliqué dans le déficit des fuseaux observé dans la schizophrénie.MÉTHODES: Une exploration électrophysiologique multisite cellule-réseau a été utilisée pour étudier, chez des rats sédatés par le pentobarbital, les effets d'une dose psychotomimétique de kétamine, un antagoniste des récepteurs au glutamate de type NMDA, dans les systèmes thalamocorticaux (TC) sensorimoteur et associatifs/limbiques/cognitifs.RÉSULTATS: Dans la condition contrôle, des fuseaux spontanés (intra-fréquence: 10-16 ondes/s) et des oscillations dans la bande de fréquence delta (1-4Hz) ont été enregistrés dans l'EEG cortical frontopariétal, dans des enregistrements extracellulaires thalamiques, dans des doubles enregistrements juxtacellulaires de neurones du noyau réticulaire thalamique (TRN) GABAergiques et TC glutamatergiques et dans des neurones TC enregistrés par dérivation intracellulaire. Les cellules TRN présentaient de façon rythmique de fortes rafales de potentiels d'action à haute fréquence (7 à 15 PAs à 200-700 Hz). Une seule administration de kétamine à faible dose a réduit de façon éphémère les fuseaux TC et les oscillations delta, amplifié les oscillations spontanées dans les bandes de fréquence gamma (30-80 Hz) et à haute fréquence (80-250 Hz), et a fait basculé le mode rafale d'émission de PAs des neurones TC et TRN vers le mode PA isolé. De plus, la kétamine a renforcé la connectivité TRN-TC dans la bande gamma. La clozapine, un antipsychotique atypique, prévient de façon systématique les effets de la kétamine sur les fuseaux, les oscillations TC delta, gamma et à haute fréquence.CONCLUSION: Ces résultats soutiennent l'hypothèse selon laquelle un hypofonctionnement des récepteurs NMDA est impliqué dans la réduction des fuseaux de sommeil et des oscillations delta. La conversion soudaine causée par la kétamine des activités TC-TRN spontanées impliquerait, au moins, à la fois le système d'activation réticulaire ascendant et la voie corticothalamique

Diminution des fuseaux du sommeil dans un modèle pour la schizophrénie

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One Click to Access Push-Triazole-Pull Fluorophores Incorporating a Pyrimidine Moiety: Structure-Photophysical Properties Relationships

International audienceUsing copper‐catalysed Huisgen 1,3‐dipolar cycloaddition, we describe the synthesis of new A‐π‐D compounds containing a pyrimidine moiety as π‐acceptor (A) and various para‐substituted benzene rings as donors (D). Structure–photophysical properties relationships revealed the triazole ring to be a better π‐conjugated linker than the triple bond

Rod-like conjugated molecules with ethynylene linkage and pyridazines moities: synthesis and light emitting properties.

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