Squarcialupi Lucia, Catarzi Daniela, Varano Flavia, Betti Marco, Falsini Matteo, Vincenzi Fabrizio, Ravani Annalisa, Ciancetta Antonella, Varani Katia, Moro Stefano, Colotta Vittoria
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy.
Eur J Med Chem. 2016 Jan 27;108:117-133. doi: 10.1016/j.ejmech.2015.11.015. Epub 2015 Nov 17.
In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor-ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2-positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4-methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3-d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described.
在先前的研究中，我们鉴定出一些7-氧代和7-酰氨基取代的吡唑并[4,3-d]嘧啶衍生物是强效且选择性的人（h）A3腺苷受体（AR）拮抗剂。在此，我们报告这类拮抗剂的结构优化，旨在实现更好的受体-配体识别。因此，在7-氧代和7-氨基衍生物的双环骨架的5位和2位引入了具有不同空间体积、柔性和亲脂性的取代基（甲基、芳基、杂芳基、苄基），并在后者的7-氨基上连接了酰基残基。所有在5位带有4-甲氧基苯基或2-噻吩基的2-苯基吡唑并[4,3-d]嘧啶-7-胺和7-酰胺均表现出高hA3亲和力和选择性。特别地，2-苯基-5-(2-噻吩基)-吡唑并[4,3-d]嘧啶-7-(4-甲氧基苯甲酰)胺25（Ki = 0.027 nM）是迄今为止报道的最有效且选择性最高的hA3拮抗剂之一。通过使用计算机辅助受体驱动方法，对获得的结合数据进行了合理化分析，并对观察到的hA3 AR亲和力的分子基础进行了关键描述。
