Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A(2B) Adenosine Receptor Antagonists

A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A(2B)AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, whi...

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Published in:Journal of medicinal chemistry 2020-07, Vol.63 (14), p.7721
Main Authors: Mallo-Abreu, Ana, Prieto-Diaz, Ruben, Jespers, Willem, Azuaje, Jhonny, Majellaro, Maria, Velando, Carmen, Garcia-Mera, Xerardo, Caamatio, Olga, Brea, Jose, Loza, Maria, I, Gutiérrez-de-Terán, Hugo, Sotelo, Eddy
Format: Article
Language:English
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Summary:A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A(2B)AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (K-i < 30 nM) and exquisite selectivity. The structure-activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA(2B)AR and the eutomer of the most attractive novel antagonist (S)-18g (K-i = 3.66 nM) was validated.
ISSN:1520-4804
0022-2623
DOI:10.1021/acs.jmedchem.0c00564