1. Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.
- Author
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Laversin A, Dufossez R, Bolteau R, Duroux R, Ravez S, Hernandez-Tapia S, Fossart M, Coevoet M, Liberelle M, Yous S, Lebègue N, and Melnyk P
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Cyclic AMP metabolism, Solubility, Protein Binding, Quinazolines chemistry, Quinazolines pharmacology, Quinazolines chemical synthesis, Adenosine A2 Receptor Antagonists chemistry, Adenosine A2 Receptor Antagonists chemical synthesis, Adenosine A2 Receptor Antagonists pharmacology, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A2A chemistry
- Abstract
The adenosine A
2A receptor (A2A R) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2A R antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 ( Ki ( h A2A R) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for h A2A R with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities ( 9x , Ki = 21 nM; 10d , Ki = 15 nM) and functional antagonist activities ( 9x , IC50 = 9 µM; 10d , IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2A R antagonists for therapeutic applications.- Published
- 2024
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