Effect of Nitrogen Atom Substitution in A3 Adenosine Receptor Binding: N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
作者： Jhonny Azuaje , Willem Jespers , Vicente Yaziji , Ana Mallo , María Majellaro
DOI: 10.1021/ACS.JMEDCHEM.7B00860
关键词: Diarylpyrimidines 、 Selectivity 、 Chemistry 、 A3 adenosine receptor binding 、 Receptor 、 Free energy perturbation 、 Binding site 、 Cricetulus 、 Stereochemistry 、 Structure–activity relationship 、 Molecular medicine 、 Drug discovery
摘要: We report the first family of 2-acetamidopyridines as potent and selective A3 adenosine receptor (AR) antagonists. The computer-assisted design was focused on bioisosteric replacement N1 atom by a CH group in previous series diarylpyrimidines. Some generated elicit an antagonistic effect with excellent affinity (Ki < 10 nM) outstanding selectivity profiles, providing alternative simpler chemical scaffold to parent In addition, using molecular dynamics free energy perturbation simulations, we elucidate second nitrogen diarylpyrimidines, which is revealed stabilizer water network binding site. discovery 2,6-diaryl-2-acetamidopyridines represents step forward search chemically simple, potent, antagonists for hA3AR, exemplifies benefits joint theoretical-experimental approach identify novel hA3AR through succinct efficient synthetic methodologies.
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