Effect of Nitrogen Atom Substitution in A3 Adenosine Receptor Binding: N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists,Journal of Medicinal Chemistry

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Effect of Nitrogen Atom Substitution in A3 Adenosine Receptor Binding: N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00860
Jhonny Azuaje , Willem Jespers ₁ , Vicente Yaziji , Ana Mallo , María Majellaro , Olga Caamaño , María I. Loza , María I. Cadavid , José Brea , Johan Åqvist ₁ , Eddy Sotelo , Hugo Gutiérrez-de-Terán ₁

Affiliation

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (K_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies.

中文翻译：

氮原子取代对A ₃腺苷受体结合的影响：N-（4,6-二芳基吡啶-2-基）乙酰胺为强效和选择性拮抗剂。

我们报告的第一个家族的2-acetamidopyridines作为有效的和选择性的A ₃腺苷受体（AR）拮抗剂。计算机辅助设计的重点是在先前的二芳基嘧啶系列中，CH基团对N1原子进行生物等位取代。某些生成的2-乙酰氨基吡啶具有极好的亲和力（K _i<10 nM）和出色的选择性，为二芳基嘧啶的母体系列提供了另一种更简单的化学支架。另外，使用分子动力学和自由能微扰模拟，我们阐明了母体二芳基嘧啶的第二氮的影响，该氮被揭示为结合位点中水网络的稳定剂。2,6-二芳基-2-乙酰氨基吡啶的发现代表了针对hA ₃ AR的化学上简单，有效和选择性拮抗剂的研究迈出的一步，并且例证了联合理论-实验方法鉴定新型hA ₃的益处。AR拮抗剂通过简洁有效的合成方法。

更新日期：2017-08-21

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