3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor: Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition,Journal of Medicinal Chemistry

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3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor: Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-29 , DOI: 10.1021/acs.jmedchem.0c01431
María Majellaro _{1,

2} , Willem Jespers ₃ , Abel Crespo _{1,

2} , María J. Núñez ₄ , Silvia Novio ₄ , Jhonny Azuaje _{1,

2} , Rubén Prieto-Díaz _{1,

2} , Claudia Gioé _{1,

2} , Belma Alispahic ₃ , José Brea ₅ , María I. Loza ₅ , Manuel Freire-Garabal ₄ , Carlota Garcia-Santiago ₄ , Carlos Rodríguez-García _{1,

2} , Xerardo García-Mera ₂ , Olga Caamaño ₂ , Christian Fernandez-Masaguer ₂ , Javier F. Sardina ₁ , Angela Stefanachi ₆ , Abdelaziz El Maatougui _{1,

2} , Ana Mallo-Abreu _{1,

2} , Johan Åqvist ₃ , Hugo Gutiérrez-de-Terán ₃ , Eddy Sotelo _{1,

2}

Affiliation

We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A_2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A_2BAR, 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 [(±)-47, and (±)-38K_i = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (K_i = 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.

中文翻译：

3，4-Dihydropyrimidin-2（1 H）-作为人类A _2B腺苷受体的拮抗剂：优化，结构-活性关系研究和对映体特异性识别。

我们提出并彻底表征大量3,4-dihydropyrimidin-2（1 H）-ones作为A _2B AR拮抗剂，这是癌症（免疫）治疗中的新兴策略。大多数化合物选择性结合A _2B AR，并通过功能性环状单磷酸腺苷实验进一步证实了许多有效的和选择性的拮抗剂。通过对GPCR进行的最详尽的自由能扰动研究之一，对该系列进行了分析，从而获得了该化学型结构与活性之间关系的准确模型。通过解析两个最有效的配体[（±）-47和（±）-38 K _i分别将其分别拆分为[10.20和23.6 nM]对映体，从而分离了相应的（S）-春黄酮上的亲和力（分别为K _i = 6.30和11.10 nM）。对代表性细胞色素（CYP3A4和CYP2D6）的作用评估显示出微不足道的抑制活性，而在三个前列腺癌细胞中的体外实验表明这对化合物表现出明显的抗转移作用。

更新日期：2021-01-14

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