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Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.
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International audience. first_pagesettingsOrder Article ReprintsOpen AccessArticleNovel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonistsby Amélie Laversin, Robin Dufossez†, Raphaël Bolteau† [ORCID] , Romain Duroux, Séverine Ravez, Sergio Hernandez-Tapia, Martin Fossart, Mathilde Coevoet[ORCID] , Maxime Liberelle, Saïd Yous, Nicolas Lebègue[ORCID] and Patricia Melnyk* [ORCID]Univ. Lille, Inserm, CHU Lille, U1172—LilNCog—Lille Neuroscience & Cognition, F-59000 Lille, France*Author to whom correspondence should be addressed.†These authors contributed equally to this work.Molecules 2024, 29(16), 3847; https://doi.org/10.3390/molecules29163847Submission received: 11 July 2024 / Revised: 31 July 2024 / Accepted: 5 August 2024 / Published: 14 August 2024(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry III)Downloadkeyboard_arrow_downBrowse FiguresReview Reports Versions NotesAbstractThe adenosine A2A receptor (A2AR) 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 A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 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 hA2AR 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 A2AR antagonists for therapeutic applications.
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