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Design, synthesis and biological evaluation of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine: Towards adenosine A2A receptor (A2A AR) antagonist
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-11-24 , DOI: 10.1016/j.ejmech.2020.113040
G. Lakshma Reddy , Rupam Sarma , Shuhao Liu , Weifeng Huang , Jinping Lei , Jiasheng Fu , Wenhao Hu

Antagonists of adenosine receptor are under exploration as potential drug candidates for treatment of neurological disorders, depression, certain cancers and potentially used as a cancer immunotherapy. Herein, we describe design and synthesis of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine (6) derivatives. All the compounds were evaluated for A2A AR antagonist activity and displayed encouraging results (IC50 9–300 nM) of A2A AR antagonist binding affinity in biochemical assay. Compound 27 exhibits good activity in A2A AR antagonist cAMP functional assay (IC50 31 nM) and further this compound shows T-cell activation at the IL-2 production assay (EC50 165 nM). Molecular docking studies were carried out to rationalize the observed binding affinity of compound 27.



中文翻译:

新型支架式苯并[4,5]咪唑并[1,2 - a ]吡嗪-1-胺的设计,合成及生物学评价:腺苷A 2A受体(A 2A AR)拮抗剂

腺苷受体的拮抗剂正在探索作为治疗神经系统疾病,抑郁症,某些癌症的潜在候选药物,并有可能用作癌症免疫疗法。在这里,我们描述了新型支架苯并[4,5]咪唑并[1,2 - a ]吡嗪-1-胺(6)衍生物的设计和合成。对所有化合物的A 2A AR拮抗剂活性进行了评估,并在生化分析中显示出令人鼓舞的A 2A AR拮抗剂结合亲和力结果(IC 50 9–300 nM)。化合物27在A 2A AR拮抗剂cAMP功能测定(IC 5031 nM),并且该化合物在IL-2产生试验(EC 50 165 nM)时显示T细胞活化。进行了分子对接研究以合理化所观察到的化合物27的结合亲和力。

更新日期:2020-12-11
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