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Targeting non-alcoholic fatty liver disease: Design, X-ray co-crystal structure and synthesis of ‘first-in-kind’ inhibitors of serine/threonine kinase25
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2022-08-24 , DOI: 10.1016/j.bmcl.2022.128950
Scarlett Kiyeleko 1 , Sofiane Hocine 1 , Giséle Mautino 2 , Mélaine Kuenemann 2 , Agata Nawrotek 3 , Linda Miallau 3 , Laurent-Michel Vuillard 2 , Olivier Mirguet 2 , Andras Kotschy 4 , Stephen Hanessian 1
Affiliation  

We describe the synthesis of a series of 3-t-butyl 5-aminopyrazole p-substituted arylamides as inhibitors of serine-threonine25 (STK25), an enzyme implicated in the progression of non-alcoholic fatty liver disease (NAFLD). Appending a p-N-pyrrolidinosulphonamide group to the arylamide group led to a ‘first-in kind’ inhibitor with IC50 = 228 nM. A co-crystal structure with STK 25 revealed productive interactions which were also reproduced using molecular docking. A new series of triazolo dihydro oxazine carboxamides of 3-t-butyl 5-aminopyrazole was not active against STK25.



中文翻译:

靶向非酒精性脂肪肝:“首创”丝氨酸/苏氨酸激酶抑制剂的设计、X 射线共晶体结构和合成25

我们描述了一系列 3-丁基 5-氨基吡唑对位取代芳基酰胺作为丝氨酸-苏氨酸 25 (STK25) 抑制剂的合成,该酶与非酒精性脂肪肝疾病 (NAFLD) 的进展有关。将 p - N-吡咯烷磺酰胺基团附加到芳基酰胺基团会产生“首创”抑制剂,IC 50  = 228 nM。与 STK 25 的共晶结构揭示了生产性相互作用,这些相互作用也使用分子对接进行了复制。3-叔丁基5-氨基吡唑的新系列三唑二氢恶嗪甲酰胺对STK25没有活性。

更新日期:2022-08-29
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