Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes
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- 作者：Abdelaziz El Maatougui ; Jhonny Azuaje ; Manuel González-Gómez ; Gabriel Miguez ; Abel Crespo ; Carlos Carbajales ; Luz Escalante ; Xerardo García-Mera ; Hugo Gutiérrez-de-Terán ; Eddy Sotelo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：59
- 期：5
- 页码：1967-1983
- 全文大小：809K
- ISSN：1520-4804
文摘
Three novel families of A2B 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) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 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 A2A receptor.