Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists

Abel Crespo; Abdelaziz El Maatougui; Pierfrancesco Biagini; Jhonny Azuaje; Alberto Coelho; José Brea; María Isabel Loza; María Isabel Cadavid; Xerardo García-Mera; Hugo Gutiérrez-de-Terán; Eddy Sotelo

doi:10.1021/ml400185v

Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists

ACS Med Chem Lett. 2013 Oct 3;4(11):1031-6. doi: 10.1021/ml400185v. eCollection 2013 Nov 14.

Affiliations

¹ Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain ; Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain.
² Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain.
³ Department of Cell and Molecular Biology, Uppsala University, Biomedical Center , Uppsala SE-75124, Sweden.
⁴ Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain ; Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain ; Center for Research in Biological Chemistry and Molecular Materials (CIQUS), Institute of Industrial Pharmacy, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , Santiago de Compostela 15782, Spain.

Abstract

We describe the discovery and optimization of 3,4-dihydropyrimidin-2(1H)-ones as a novel family of (nonxanthine) A2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure-activity and structure-selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA2B AdoR affinity and remarkable selectivity profiles.

Keywords: 3,4-dihydropyrimidin-2(1H)-ones; A2B receptor antagonists; Adenosine antagonists; Biginelli reaction.