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：

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基于结构的N-（3-（（1H-吡唑并[3,4-b]吡啶基-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。

第一类高选择性ZAK抑制剂被设计为一系列N-（3-（（1H-吡唑并[3,4-b]吡啶基-5-基]乙炔基）乙炔基）苯磺酰胺。代表性化合物3h强烈抑制激酶活性ZAK的IC50为3.3 nM，并在体外和体内剂量依赖性地抑制ZAK下游信号的激活，但对于大多数评估的403种非突变激酶而言，其效价明显降低；化合物3h对心脏肥大也具有口服治疗作用在自发性高血压大鼠模型中。