14 research outputs found
New targets for the study and development of new pharmacological tools for the treatment of neuropathic pain
Les douleurs neuropathiques dĂ©signent une hypersensibilitĂ© du systĂšme nerveux central sensoriel. Câest une maladie chronique et handicapante qui touche environ 6% de la population française. Cependant, Ă lâheure actuelle, il nâexiste pas de traitement spĂ©cifique et efficace. Dans le cadre de cette thĂšse, nous avons utilisĂ© deux stratĂ©gies diffĂ©rentes afin de dĂ©velopper des outils pharmacologiques originaux pour traiter ces douleurs : une approche phĂ©notypique autour de deux inhibiteurs de la surproduction de TNFα (un dĂ©rivĂ© de 2-aminopyrimidine et un dĂ©rivĂ© de pyridin-2-yl guanidine) et une approche molĂ©culaire autour du MY 5445 (un inhibiteur de PDE5 dĂ©rivĂ© de phtalazine). En particulier, notre travail sâest basĂ© sur la conception, la synthĂšse et lâĂ©tude des relations structure-activitĂ© autour de ces diffĂ©rents hits et nous avons obtenu des composĂ©s efficaces par voie i.p. ou per-os sur un modĂšle murin de douleurs neuropathiques.En parallĂšle de ce travail de pharmacologie, nous avons dĂ©veloppĂ© diffĂ©rents systĂšmes catalytiques (Pd, Cu) en milieu micellaire afin de former des liaisons C-N Ă tempĂ©rature quasi-ambiante.Neuropathic pains correspond to a central sensory nervous system hypersensitivity. It is a chronic and disabling disease, which touch around 6% of the French population. Nowadays, there is no specific and efficient treatment. In my PhD project, we used two different strategies in order to develop innovative pharmacological tools to treat those pains: a phenotypic approach around two TNFα overproduction inhibitor (a 2-aminopyrimidine derivative and a pyridin-2-yl guanidine derivative) and a molecular approach around MY 5445 (a phthalazine PDE5 inhibitor). Our work was based on the design, synthesis and structure-activity relationship study around various hits and we obtained compounds i.p. and orally effective on a murin neuropathic pain model.In parallel to this pharmacological work, we developed different catalytic systems (Pd, Cu) under micellar conditions to form C-N bonds at almost room temperature
Nouvelles cibles pour l'étude et le développement d'outils pharmacologiques originaux pour le traitement des douleurs neuropathiques
Neuropathic pains correspond to a central sensory nervous system hypersensitivity. It is a chronic and disabling disease, which touch around 6% of the French population. Nowadays, there is no specific and efficient treatment. In my PhD project, we used two different strategies in order to develop innovative pharmacological tools to treat those pains: a phenotypic approach around two TNFα overproduction inhibitor (a 2-aminopyrimidine derivative and a pyridin-2-yl guanidine derivative) and a molecular approach around MY 5445 (a phthalazine PDE5 inhibitor). Our work was based on the design, synthesis and structure-activity relationship study around various hits and we obtained compounds i.p. and orally effective on a murin neuropathic pain model.In parallel to this pharmacological work, we developed different catalytic systems (Pd, Cu) under micellar conditions to form C-N bonds at almost room temperature.Les douleurs neuropathiques dĂ©signent une hypersensibilitĂ© du systĂšme nerveux central sensoriel. Câest une maladie chronique et handicapante qui touche environ 6% de la population française. Cependant, Ă lâheure actuelle, il nâexiste pas de traitement spĂ©cifique et efficace. Dans le cadre de cette thĂšse, nous avons utilisĂ© deux stratĂ©gies diffĂ©rentes afin de dĂ©velopper des outils pharmacologiques originaux pour traiter ces douleurs : une approche phĂ©notypique autour de deux inhibiteurs de la surproduction de TNFα (un dĂ©rivĂ© de 2-aminopyrimidine et un dĂ©rivĂ© de pyridin-2-yl guanidine) et une approche molĂ©culaire autour du MY 5445 (un inhibiteur de PDE5 dĂ©rivĂ© de phtalazine). En particulier, notre travail sâest basĂ© sur la conception, la synthĂšse et lâĂ©tude des relations structure-activitĂ© autour de ces diffĂ©rents hits et nous avons obtenu des composĂ©s efficaces par voie i.p. ou per-os sur un modĂšle murin de douleurs neuropathiques.En parallĂšle de ce travail de pharmacologie, nous avons dĂ©veloppĂ© diffĂ©rents systĂšmes catalytiques (Pd, Cu) en milieu micellaire afin de former des liaisons C-N Ă tempĂ©rature quasi-ambiante
New targets for the study and development of new pharmacological tools for the treatment of neuropathic pain
Les douleurs neuropathiques dĂ©signent une hypersensibilitĂ© du systĂšme nerveux central sensoriel. Câest une maladie chronique et handicapante qui touche environ 6% de la population française. Cependant, Ă lâheure actuelle, il nâexiste pas de traitement spĂ©cifique et efficace. Dans le cadre de cette thĂšse, nous avons utilisĂ© deux stratĂ©gies diffĂ©rentes afin de dĂ©velopper des outils pharmacologiques originaux pour traiter ces douleurs : une approche phĂ©notypique autour de deux inhibiteurs de la surproduction de TNFα (un dĂ©rivĂ© de 2-aminopyrimidine et un dĂ©rivĂ© de pyridin-2-yl guanidine) et une approche molĂ©culaire autour du MY 5445 (un inhibiteur de PDE5 dĂ©rivĂ© de phtalazine). En particulier, notre travail sâest basĂ© sur la conception, la synthĂšse et lâĂ©tude des relations structure-activitĂ© autour de ces diffĂ©rents hits et nous avons obtenu des composĂ©s efficaces par voie i.p. ou per-os sur un modĂšle murin de douleurs neuropathiques.En parallĂšle de ce travail de pharmacologie, nous avons dĂ©veloppĂ© diffĂ©rents systĂšmes catalytiques (Pd, Cu) en milieu micellaire afin de former des liaisons C-N Ă tempĂ©rature quasi-ambiante.Neuropathic pains correspond to a central sensory nervous system hypersensitivity. It is a chronic and disabling disease, which touch around 6% of the French population. Nowadays, there is no specific and efficient treatment. In my PhD project, we used two different strategies in order to develop innovative pharmacological tools to treat those pains: a phenotypic approach around two TNFα overproduction inhibitor (a 2-aminopyrimidine derivative and a pyridin-2-yl guanidine derivative) and a molecular approach around MY 5445 (a phthalazine PDE5 inhibitor). Our work was based on the design, synthesis and structure-activity relationship study around various hits and we obtained compounds i.p. and orally effective on a murin neuropathic pain model.In parallel to this pharmacological work, we developed different catalytic systems (Pd, Cu) under micellar conditions to form C-N bonds at almost room temperature
Troubles du sommeil et migraine (physiologie et traitements)
POITIERS-BU MĂ©decine pharmacie (861942103) / SudocSudocFranceF
On water N -arylation of oxetanylamines for the preparation of N -aryl-oxetanylamines; potentially useful aryl-amide isosteres
International audienceA Pd cross-coupling approach for the synthesis of N-aryl-oxetanyl-amines has been developed. This method provides new building blocks potentially useful in medicinal chemistry as amide bioisosteres. The reactions are conducted in water employing the renewable feedstock surfactant TPGS-750-M
d -Glucose: An Efficient Reducing Agent for a Copper(II)-Mediated Arylation of Primary Amines in Water
International audienc
Structure-Guided Identification of a Small Molecule That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria
The anaerobic gut microbial pathway that converts choline into trimethylamine (TMA) is broadly linked to human disease. Here, we describe the discovery that betaine aldehyde inhibits TMA production from choline by human gut bacterial isolates and a complex gut community. In vitro assays and a crystal structure suggest betaine aldehyde targets the gut microbial enzyme choline TMA-lyase (CutC). In our system, we do not observe activity for the previously reported CutC inhibitor 3,3-dimethylbutanol (DMB). The workflow we establish for identifying and characterizing betaine aldehyde provides a framework for developing additional inhibitors of gut microbial choline metabolism, including therapeutic candidates
Efficient and Mild Ullmann-Type N-Arylation of Amides, Carbamates, and Azoles in Water
International audienc
Design, Synthesis and Biological Evaluation of Arylpyridin-2-yl Guanidine Derivatives and Cyclic Mimetics as Novel MSK1 Inhibitors. An Application in an Asthma Model
Mitogen- and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 µM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 µM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma
Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels
Acid-sensing ion
channels (ASICs) are neuronal Na<sup>+</sup>-selective
ion channels that open in response to extracellular acidification.
They are involved in pain, fear, learning, and neurodegeneration after
ischemic stroke. 2-Guanidine-4-methylquinazoline (GMQ) was recently
discovered as the first nonproton activator of ASIC3. GMQ is of interest
as a gating modifier and pore blocker of ASICs. It has however a low
potency, and exerts opposite effects on ASIC1a and ASIC3. To further
explore the molecular mechanisms of GMQ action, we have used the guanidinium
moiety of GMQ as a scaffold and tested the effects of different GMQ
derivatives on the ASIC pH dependence and maximal current. We report
that GMQ derivatives containing quinazoline and quinoline induced,
as GMQ, an alkaline shift of the pH dependence of activation in ASIC3
and an acidic shift in ASIC1a. Another group of 2-guanidinopyridines
shifted the pH dependence of both ASIC1a and ASIC3 to more acidic
values. Several compounds induced an alkaline shift of the pH dependence
of ASIC1a/2a and ASIC2a/3 heteromers. Compared to GMQ, guanidinopyridines
showed a 20-fold decrease in the IC<sub>50</sub> for ASIC1a and ASIC3
current inhibition at pH 5. Strikingly, 2-guanidino-quinolines and
-pyridines showed a concentration-dependent biphasic effect that resulted
at higher concentrations in ASIC1a and ASIC3 inhibition (IC<sub>50</sub> > 100 ÎŒM), while causing at lower concentration a potentiation
of ASIC1a, but not ASIC3 currents (EC<sub>50</sub> â 10 ÎŒM).
In conclusion, we describe a new family of small molecules as ASIC
ligands and identify an ASIC subtype-specific potentiation by a subgroup
of these compounds