A series of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compound 3h strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compound 3h also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model.

中文翻译：

---

基于结构的 N-(3-((1H-吡唑并[3,4-b]吡啶-5-基)乙炔基)苯磺酰胺作为选择性亮氨酸拉链和无菌-α 基序激酶 (ZAK) 抑制剂的设计。


一系列N-(3-((1H-吡唑并[3,4-b]吡啶-5-基)乙炔基)苯磺酰胺被设计为第一类高选择性ZAK抑制剂。代表化合物3h强烈抑制激酶活性ZAK 的 IC50 为 3.3 nM，并且在体外和体内剂量依赖性地抑制 ZAK 下游信号的激活，而它对于所评估的大多数 403 非突变激酶的效力明显较低。化合物 3h 也表现出对心脏肥大的口服治疗作用。在自发性高血压大鼠模型中。