3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor: Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
| Autor: | Silvia Novío, Christian Fernandez-Masaguer, Jhonny Azuaje, Hugo Gutiérrez-de-Terán, Olga Caamaño, Carlos Rodríguez-García, Manuel Freire-Garabal, Angela Stefanachi, Carlota Garcia-Santiago, Willem Jespers, Abel Crespo, María Isabel Loza, Javier F Sardina, José Brea, Johan Åqvist, Eddy Sotelo, Abdelaziz El Maatougui, Ana Mallo-Abreu, Rubén Prieto-Díaz, María Majellaro, Belma Alispahic, Xerardo García-Mera, María José Núñez, Claudia Gioé |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Stereochemistry Chemistry 01 natural sciences Adenosine receptor In vitro 0104 chemical sciences Free energy perturbation 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Stereospecificity Drug Discovery Molecular Medicine Structure–activity relationship Cyclic adenosine monophosphate Enantiomer 030304 developmental biology G protein-coupled receptor |
| Zdroj: | Journal of Medicinal Chemistry. 64:458-480 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure-activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect. |
| Databáze: | OpenAIRE |
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