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.

中文翻译：

---

氮步行法探索一系列有效的A2B腺苷受体拮抗剂的生物等效取代。

使用氮游走法已经对一系列有效的A _2B AR拮抗剂中的呋喃和噻吩核的生物立体替代物进行了系统的研究。收集了42种新颖的4-取代-2-甲基-1,4-二氢苯并[4,5]咪唑并[1,2 - a ]嘧啶-3-羧酸烷基酯，它们在4位含有18个不同的五角杂环骨架。综合和评估。这项研究使得能够鉴定结合了显着亲和力（K _i<30 nM）和精湛的选择性。基于受体驱动的对接模型并包括系统的自由能扰动（FEP）研究，通过分子建模研究证实了所确定的构效关系（SAR）趋势。在优化配体中对CYP3A4和CYP2D6抑制活性的初步评估分别显示弱和可忽略的活性。验证了h A _2B AR与最有吸引力的新型拮抗剂（S）-18g（K _i = 3.66 nM）的eutomer之间的立体定向相互作用。