Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists

Ana Mallo-Abreu; Rubén Prieto-Díaz; Willem Jespers; Jhonny Azuaje; Maria Majellaro; Carmen Velando; Xerardo García-Mera; Olga Caamaño; José Brea; María I Loza; Hugo Gutiérrez-de-Terán; Eddy Sotelo

doi:10.1021/acs.jmedchem.0c00564

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

J Med Chem. 2020 Jul 23;63(14):7721-7739. doi: 10.1021/acs.jmedchem.0c00564. Epub 2020 Jul 7.

Authors

Ana Mallo-Abreu, Rubén Prieto-Díaz, Willem Jespers¹, Jhonny Azuaje, Maria Majellaro, Carmen Velando, Xerardo García-Mera, Olga Caamaño, José Brea², María I Loza², Hugo Gutiérrez-de-Terán¹, Eddy Sotelo

Affiliations

¹ Department of Cell and Molecular Biology, Uppsala University, Uppsala SE 75124, Sweden.
² Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

PMID: 32573250
DOI: 10.1021/acs.jmedchem.0c00564

Abstract

A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A_2BAR 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_2BAR and the eutomer of the most attractive novel antagonist (S)-18g (K_i = 3.66 nM) was validated.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine A2 Receptor Antagonists / chemical synthesis
Adenosine A2 Receptor Antagonists / metabolism
Adenosine A2 Receptor Antagonists / pharmacology*
Animals
CHO Cells
Cell Line, Tumor
Cricetulus
Cytochrome P-450 CYP2D6 Inhibitors / chemical synthesis
Cytochrome P-450 CYP2D6 Inhibitors / metabolism
Cytochrome P-450 CYP2D6 Inhibitors / pharmacology
Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
Cytochrome P-450 CYP3A Inhibitors / metabolism
Cytochrome P-450 CYP3A Inhibitors / pharmacology
Humans
Imidazoles / chemical synthesis
Imidazoles / metabolism
Imidazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Receptor, Adenosine A2B / metabolism*
Stereoisomerism
Structure-Activity Relationship

Substances

ADORA2B protein, human
Adenosine A2 Receptor Antagonists
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Imidazoles
Pyrimidines
Receptor, Adenosine A2B