异恶唑类似物与系统 xc-转运体结合：结构-活性关系和药效团模型。
Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.
机构信息
NIH COBRE Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, USA.
出版信息
Bioorg Med Chem. 2010 Jan 1;18(1):202-13. doi: 10.1016/j.bmc.2009.11.001. Epub 2009 Nov 10.
Abstract
Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships.
摘要
制备了氨基酸甲氨基异恶唑丙酸（AMPA）类似物，包括亲脂性类似物，采用侧向金属化和亲电淬灭，在 System xc- 中进行了评估。5-萘乙基-（16）和 5-萘甲氧基甲基-（17）类似物在固态中均采用 E-构象，但前者在 System xc- 中具有较强的结合力，而后者几乎没有活性。最有效的类似物是氨基酸萘基-ACPA 7g 和酰肼羧酸 11e Y=Y'=3,5-（CF(3))(2)，它们都能与内源性底物胱氨酸一样有效地抑制 System xc- 转运体摄取谷氨酸，而相反的是，闭合的异噁唑[3,4-d]哒嗪酮 13 的活性则显著降低。构建了一个初步的药效团模型，以深入了解类似物的结构-活性关系。
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