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首页> 外文期刊>Bioorganic and Medicinal Chemistry >4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.
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4-amino-5-aryl-6-arylethynylpyrimidines: structure-activity relationships of non-nucleoside adenosine kinase inhibitors.

机译：4-氨基-5-芳基-6-芳基乙炔基嘧啶：非核苷腺苷激酶抑制剂的结构活性关系。

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摘要

A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4 -ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin -4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
机译：报道了一系列非核苷腺苷激酶（AK）抑制剂。这些抑制剂源自5-（3-溴苯基）-7-（6-吗啉-4-基吡啶基-3-基）吡啶并[2，3-d]嘧啶-4-基胺（ABT-702）的修饰。在该修饰中，关键在于鉴定能够近似于嘧啶环与在ABT-702的C（7）处的芳基之间发现的空间排列的接头。对潜在接头的搜索导致发现乙炔部分作为合适的支架。假设相对于杂环碱基的取向，芳基乙炔，ABT-702和腺苷以相似的方式结合至AK的活性位点（封闭形式）。尽管基于此假设发现了有效的乙炔类似物，但揭示了5-（4-二甲基氨基苯基）-6-（6-吗啉-4-基吡啶3基乙炔基）嘧啶-4-基胺（16a）的X射线晶体结构与腺苷相反的结合方向。此外，该化合物与AK的独特开放构象紧密结合。讨论了构效关系，独特的配体取向和蛋白质构象。

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