Development of novel 2,4-bispyridyl thiophene–based compounds as highly potent and selective Dyrk1A inhibitors. Part I: Benzamide and benzylamide derivatives
作者:Sarah S. Darwish、Mohammad Abdel-Halim、Mohamed Salah、Ashraf H. Abadi、Walter Becker、Matthias Engel
DOI:10.1016/j.ejmech.2018.07.050
日期:2018.9
effects especially over long treatment periods. Herein, we describe the design and synthesis of a series of amide functionalized 2,4-bispyridyl thiophene compounds, of which the 4-fluorobenzyl amide derivative (31b) displayed the highest potency against Dyrk1A and remarkable selectivity over closely related kinases (IC50: Dyrk1A = 14.3 nM; Dyrk1B = 383 nM, Clk1 > 2 μM). This degree of selectivity over
蛋白激酶Dyrk1A调节与阿尔茨海默氏病(AD)的发生或发展相关的多个过程,例如通过tau蛋白,淀粉样前体蛋白(APP)的磷酸化以及与tau pre-mRNA的选择性剪接相关的蛋白。因此,Dyrk1A已被提议作为治疗AD的潜在靶标。但是,对同一个蛋白激酶家族的其他紧密相关的激酶(例如Dyrk1B和Dyrk2)或其他家族的激酶(例如Clk1)的共抑制作用限制了Dyrk1A抑制剂的使用,因为这可能会导致无法预料的副作用,尤其是在长期治疗中时期。在这里,我们描述了一系列酰胺官能化的2,4-双吡啶基噻吩化合物的设计和合成,其中4-氟苄基酰胺衍生物(31b)显示出对Dyrk1A的最高效力,并且比紧密相关的激酶具有显着的选择性(IC 50:Dyrk1A = 14.3 nM; Dyrk1B = 383 nM,Clk1> 2μM)。迄今为止,很少能达到对频繁击中目标的选择性。此外,31b在完整细胞中以高效率抑制了Dyrk1A(IC