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.
Abel Crespo  1 ,  Abdelaziz El Maatougui  1 ,  Pierfrancesco Biagini  2 ,  Jhonny Azuaje  1 ,  Alberto Coelho  1 ,  José Brea  2 ,  María Isabel Loza  2 ,  María Isabel Cadavid  2 ,  Xerardo García-Mera  2 ,  Hugo Gutiérrez-de-Terán  3 ,  Eddy Sotelo  4
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.
PMID: 24900602 DOI: 10.1021/ml400185v
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.
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