Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste , Piazzale Europa 1, 34127 Trieste, Italy.
J Med Chem. 2014 Jul 24;57(14):6210-25. doi: 10.1021/jm500752h. Epub 2014 Jul 11.
The structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA2A and hA3 ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA2A antagonists (compound 12: hA2A AR Ki=3.32 nM; hA1/hA2A=55.6; hA2A/hA3=0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki=4.14 nM, hA1/hA3=236; hA2A/hA3=25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR.
我们探索了新型 5,8-二取代-1,2,4-三唑并[1,5-c]嘧啶类化合物作为腺苷受体 (AR) 拮抗剂的构效关系 (SAR)。所有合成的化合物都表现出对 hA2A 和 hA3 AR 的亲和力，这取决于 5 位和 8 位的取代模式。特别是，5 位带有游离氨基且 8 位带有乙氧羰基，会导致强效且相当选择性的 hA2A 拮抗剂 (化合物 12：hA2A AR Ki=3.32 nM；hA1/hA2A=55.6；hA2A/hA3=0.01)，而在 5 位引入甲基氨基则会在 hA3 AR 上产生良好的结合特性 (化合物 23：hA3 AR Ki=4.14 nM，hA1/hA3=236；hA2A/hA3=25)。通过基于受体的计算方法，我们确定了 1,2,4-三唑并[1,5-c]嘧啶 (TP) 骨架 5 位和 8 位取代的最有利取向，并据此阐明了观察到的 SAR。
