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1.
Eur J Med Chem ; 241: 114620, 2022 Nov 05.
Article in English | MEDLINE | ID: mdl-35933788

ABSTRACT

The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A2AAR antagonists. Among them, one compound showed a high affinity towards A2AAR (21a, Ki = 20 nM). We crystallized this ligand in complex with A2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.


Subject(s)
Adenosine A2 Receptor Antagonists , Purinergic P1 Receptor Antagonists , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Ligands , Molecular Docking Simulation , Purinergic P1 Receptor Antagonists/pharmacology , Quinazolines/pharmacology , Receptor, Adenosine A2A/chemistry , Structure-Activity Relationship
2.
Eur J Med Chem ; 189: 112078, 2020 Mar 01.
Article in English | MEDLINE | ID: mdl-32004937

ABSTRACT

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.


Subject(s)
Acetamides/chemistry , Phthalazines/chemistry , Quinazolines/chemistry , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Acetamides/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , HEK293 Cells , Humans , Ligands , Phthalazines/metabolism , Quinazolines/metabolism , Structure-Activity Relationship
3.
Bioorg Med Chem ; 26(12): 3296-3307, 2018 07 23.
Article in English | MEDLINE | ID: mdl-29753566

ABSTRACT

Imidazo[1,2a]pyridines have gained much interest in the field of medicinal chemistry research. In the aim of accessing new privileged structure, we decided to design and synthesize 8-aminated-imidazo[1,2a]pyridines substituted on positions 2 and 6. This scaffold, rarely found in the literature, was obtained via palladium-catalyzed coupling reactions (Suzuki reaction or N-hydroxysuccinimidyl activated ester method) and tested on adenosine receptor A2A. We demonstrated how incorporation of an exocyclic amine enhanced affinity towards this receptor while maintaining low cytotoxicity.


Subject(s)
Drug Design , Pyridines/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/metabolism , Adenosine A2 Receptor Antagonists/pharmacology , Binding Sites , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , HEK293 Cells , Humans , Molecular Docking Simulation , Palladium/chemistry , Protein Structure, Tertiary , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/metabolism , Structure-Activity Relationship
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