7 results on '"Damien Hedou"'
Search Results
2. Computer-aided design, synthesis, and biological evaluation of [4.3.0] bicyclic prolyl oligopeptidase and fibroblast activation protein-α dual inhibitors
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Jessica Plescia, Caroline Dufresne, Anthony Mittermaier, Maud Pousse, Damien Hedou, Anne Labarre, and Nicolas Moitessier
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Biochemistry ,Bicyclic molecule ,Fibroblast activation protein, alpha ,Docking (molecular) ,Covalent bond ,Chemistry ,Peptidomimetic ,medicine ,Oligopeptidase ,Cancer ,medicine.disease ,In vitro ,3. Good health - Abstract
We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to a dual inhibitor equipotent to the only anti-POP/FAP drug that ever-reached clinical trials.
- Published
- 2021
3. Novel Multitarget-Directed Ligands (MTDLs) with Acetylcholinesterase (AChE) Inhibitory and Serotonergic Subtype 4 Receptor (5-HT 4 R) Agonist Activities As Potential Agents against Alzheimer’s Disease: The Design of Donecopride
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Sylvie Claeysen, Michel Boulouard, Emmanuelle Dubost, Valentine Bouet, David Genest, Céline Ballandonne, Rémi Legay, Patrick Dallemagne, Damien Hedou, Samir Yahiaoui, Thomas Freret, Jana Sopkova-de Oliveira Santos, François Dauphin, Katia Hamidouche, Patrizia Giannoni, Florence Gaven, Christophe Rochais, Sophie Corvaisier, Aurélie Malzert-Fréon, Cédric Lecoutey, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Groupe Mémoire et Plasticité comportementale (GMPc), This work was supported by funding from the Conseil Régional de Basse Normandie, France (Dispositif de Soutien aux Projets de Recherche Emergents), French Agence Nationale de la Recherche Projects MALAD ANR-12-JS007-0012-01 and ADAMGUARD ANR-12-BSV4-008-01, and Ligue Européenne Contre la Maladie d’Alzheimer Grant 12721., ANR-12-JS07-0012,MALAD,Developpement de Ligands pluriactifs d'intérêt potentiel dans le traitement de la maladie d'Alzheimer(2012), ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012), Cailly, Thomas, Jeunes Chercheuses et Jeunes Chercheurs - Developpement de Ligands pluriactifs d'intérêt potentiel dans le traitement de la maladie d'Alzheimer - - MALAD2012 - ANR-12-JS07-0012 - JC - VALID, BLANC - Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP - - ADAMGUARD2012 - ANR-12-BSV4-0008 - BLANC - VALID, and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
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Agonist ,Male ,medicine.drug_class ,Aché ,[CHIM.THER] Chemical Sciences/Medicinal Chemistry ,Guinea Pigs ,Drug Evaluation, Preclinical ,Mice, Inbred Strains ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Serotonergic ,Inhibitory postsynaptic potential ,Crystallography, X-Ray ,Ligands ,Alzheimer's Disease ,MTDL ,chemistry.chemical_compound ,Serotonin 5-HT4 Receptor Agonists ,Structure-Activity Relationship ,Piperidines ,In vivo ,Alzheimer Disease ,Drug Discovery ,medicine ,Toxicity Tests, Acute ,Structure–activity relationship ,Animals ,Humans ,Computer Simulation ,Molecular Targeted Therapy ,Receptor ,Aniline Compounds ,Acetylcholinesterase ,language.human_language ,3. Good health ,Donecopride ,Mice, Inbred C57BL ,Memory, Short-Term ,chemistry ,Drug Design ,language ,Molecular Medicine ,Cholinesterase Inhibitors ,Receptors, Serotonin, 5-HT4 ,5-HT4 Receptors - Abstract
International audience; In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer’s disease.
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- 2015
4. Discovery of a new antileishmanial hit in 8-nitroquinoline series
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Patrick Dallemagne, Thierry Cresteil, Florence Gaven, Sylvie Claeysen, Patrizia Giannoni, Sophie Corvaisier, Michel Boulouard, Céline Ballandonne, Aurélie Malzert-Fréon, Cédric Lecoutey, Thomas Freret, Christophe Rochais, Valentine Bouet, Damien Hedou, Serge Mignani, and Marc Since
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Leishmania donovani ,Antiprotozoal Agents ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Mice ,parasitic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,Amastigote ,IC50 ,Miltefosine ,Life Cycle Stages ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Nitroquinolines ,General Medicine ,Hep G2 Cells ,biology.organism_classification ,In vitro ,0104 chemical sciences ,3. Good health ,Leishmania infantum ,Pharmacophore ,medicine.drug ,Pentamidine - Abstract
A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.
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- 2012
5. Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part II
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Alicia Foucourt, Damien Hédou, Carole Dubouilh-Benard, Angélique Girard, Thierry Taverne, Anne-Sophie Casagrande, Laurent Désiré, Bertrand Leblond, and Thierry Besson
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thiazolo[5,4-f]quinazolines ,kinase inhibitors ,DYRK1A ,DYRK1B ,microwave-assisted chemistry ,Dimroth rearrangement ,EHT 5372 ,EHT 6840 ,EHT 1610 ,EHT 9851 ,EHT 3356 ,Organic chemistry ,QD241-441 - Abstract
The convenient synthesis of a focused library (forty molecules) of novel 6,6,5-tricyclic thiazolo[5,4-f]quinazolines was realized mainly under microwave irradiation. A novel 6-aminobenzo[d]thiazole-2,7-dicarbonitrile (1) was used as a versatile molecular platform for the synthesis of various derivatives. Kinase inhibition, of the obtained final compounds, was evaluated on a panel of two kinases (DYRK1A/1B) together with some known reference DYRK1A and DYRK1B inhibitors (harmine, TG003, NCGC-00189310 and leucettine L41). Compound IC50 values were obtained and compared. Five of the novel thiazolo[5,4-f]quinazoline derivatives prepared, EHT 5372 (8c), EHT 6840 (8h), EHT 1610 (8i), EHT 9851 (8k) and EHT 3356 (9b) displayed single-digit nanomolar or subnanomolar IC50 values and are among the most potent DYRK1A/1B inhibitors disclosed to date. DYRK1A/1B kinases are known to be involved in the regulation of various molecular pathways associated with oncology, neurodegenerative diseases (such as Alzheimer disease, AD, or other tauopathies), genetic diseases (such as Down Syndrome, DS), as well as diseases involved in abnormal pre-mRNA splicing. The compounds described in this communication constitute a highly potent set of novel molecular probes to evaluate the biology/pharmacology of DYR1A/1B in such diseases.
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- 2014
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6. Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation
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Damien Hédou, Carole Dubouilh-Benard, Nadège Loaëc, Laurent Meijer, Corinne Fruit, and Thierry Besson
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Hügershoff reaction ,thiazolo[5,4-f]quinazolin-9(8H)-ones ,microwave-assisted synthesis ,protein kinases ,CDK5 ,GSK-3 ,CLK1 ,CK1 ,DYRK1A ,Organic chemistry ,QD241-441 - Abstract
A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.
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- 2016
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7. Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases
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Damien Hédou, Julien Godeau, Nadège Loaëc, Laurent Meijer, Corinne Fruit, and Thierry Besson
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thiazolo[5,4-f]quinazolin-9(8H)-ones ,multi-target-directed ligand ,protein kinases ,microwave-assisted synthesis ,CDK5 ,GSK-3 ,CLK1 ,CK1 ,DYRK1A. ,Organic chemistry ,QD241-441 - Abstract
A library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer’s disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinases.
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- 2016
- Full Text
- View/download PDF
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