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7-(脯氨醇-N-基)-2-苯基氨基噻唑并[5,4-d]嘧啶作为新型A2A腺苷受体非核苷类部分激动剂的发现：基于分子模拟的预测

Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A2A Adenosine Receptor: Prediction from Molecular Modeling.

作者信息

Bharate Sandip B, Singh Baljinder, Kachler Sonja, Oliveira Ana, Kumar Vikas, Bharate Sonali S, Vishwakarma Ram A, Klotz Karl-Norbert, Gutiérrez de Terán Hugo

机构信息

Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg , Versbacher Strasse 9, D-97078 Würzburg, Germany.

Department of Cell and Molecular Biology, Uppsala University , Box 596, SE-751 24 Uppsala, Sweden.

出版信息

J Med Chem. 2016 Jun 23;59(12):5922-8. doi: 10.1021/acs.jmedchem.6b00552. Epub 2016 Jun 7.

DOI:10.1021/acs.jmedchem.6b00552
PMID:27227326
Abstract

We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A2A adenosine receptor (A2AAR). Molecular-modeling indicated that the (S)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties.

摘要

我们描述了7-(脯氨醇-N-基)-2-苯基氨基-噻唑并[5,4-d]嘧啶作为A2A腺苷受体（A2AAR）非核苷部分激动剂的一种新型化学类型的鉴定。分子建模表明，(S)-2-羟基亚甲基-吡咯烷可以模拟激动剂核糖的相互作用，这表明这类化合物可能具有激动特性。这一点在对A2AAR的功能测定中得到了证实，在该测定中它们的效力可能与2-羟基亚甲基部分的存在有关。此外，最佳化合物表现出有前景的亲和力、选择性概况和物理化学性质。

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