Discovery of Potent and Highly Selective A(2B) Adenosine Receptor Antagonist Chemotypes
2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, 1967-1983 p.Article in journal (Refereed) PublishedText
Three novel families of A(2B) adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin,2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A(2B) ligand that exhibits complete selectivity toward A(1), A(2A), and A(3) receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A(2A) receptor.
Place, publisher, year, edition, pages
2016. Vol. 59, no 5, 1967-1983 p.
Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:uu:diva-283768DOI: 10.1021/acs.jmedchem.5b01586ISI: 000372043400023PubMedID: 26824742OAI: oai:DiVA.org:uu-283768DiVA: diva2:919668