合成并评价异噻唑并[4,5-d]嘧啶作为细胞周期蛋白 G 相关激酶（GAK）抑制剂。
Synthesis and evaluation of isothiazolo[4,5-]pyridines as cyclin G-associated kinase (GAK) inhibitors.
机构信息
KU Leuven, Department of Chemistry, Sustainable Chemistry for Metals and Molecules, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Herestraat 49, box 1030, 3000 Leuven, Belgium.
出版信息
Org Biomol Chem. 2024 Sep 18;22(36):7373-7389. doi: 10.1039/d4ob00908h.
Isothiazolo[4,3-]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5-]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5-]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5-]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.
噻唑并[4,3-]吡啶类化合物已被广泛探索作为细胞周期蛋白 G 相关激酶（GAK）的抑制剂。为了扩展构效关系研究并发现其他作为 GAK 抑制剂的类药性化合物，我们探索了密切相关的噻唑并[4,5-]吡啶骨架。开发了一种简便高效的合成方法，可获得 3,5-和 3,6-二卤代噻唑并[4,5-]吡啶作为关键构建块。用各种取代基进行了区域选择性官能化。新合成的噻唑并[4,5-]吡啶均没有作为 GAK 抑制剂的活性。应用分子模拟来合理化它们作为 GAK 结合物的无活性。
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