3,4-Dihydropyrimidin-2(1 H )-ones as Antagonists of the Human A 2B Adenosine Receptor: Optimization, Structure-Activity Relationship Studies, and Enantiospecific Recognition

• Published in: Journal of medicinal chemistry 2021-01, Vol.64 (1), p.458-480
• Main Authors: Majellaro, María, Jespers, Willem, Crespo, Abel, Núñez, María J, Novio, Silvia, Azuaje, Jhonny, Prieto-Díaz, Rubén, Gioé, Claudia, Alispahic, Belma, Brea, José, Loza, María I, Freire-Garabal, Manuel, Garcia-Santiago, Carlota, Rodríguez-García, Carlos, García-Mera, Xerardo, Caamaño, Olga, Fernandez-Masaguer, Christian, Sardina, Javier F, Stefanachi, Angela, El Maatougui, Abdelaziz, Mallo-Abreu, Ana, Åqvist, Johan, Gutiérrez-de-Terán, Hugo, Sotelo, Eddy
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Antagonists - metabolism; Adenosine A2 Receptor Antagonists - pharmacology; Animals; CHO Cells; Cricetulus; Cyclic AMP - metabolism; HEK293 Cells; HeLa Cells; Humans; Models, Molecular; Neoplasm Metastasis - prevention & control; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacology; Radioligand Assay; Receptor, Adenosine A2B - drug effects; Receptor, Adenosine A2B - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01431

We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1 )-ones as A AR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A AR, 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 [(±)- , and (±)- = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding ( )-eutomers ( = 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.