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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and biological evaluation of new creatine fatty esters revealed Dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency
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Synthesis and biological evaluation of new creatine fatty esters revealed Dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency

机译：新型肌酸脂肪酯的合成和生物学评估表明十二烷基肌酸酯是治疗肌酸转运蛋白缺乏症的有前途的候选药物

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The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.
机译：肌酸转运蛋白缺乏症是一种神经疾病，由肌酸转运蛋白SLC6A8的损伤引起，导致智力低下，与脑内肌酸的完全缺乏和神经元细胞的细胞能量摄动有关。一种治疗假说是施用亲脂性肌酸衍生物，其被认为（1）具有更好的细胞膜通透性，（2）不依赖于SLC6A8的活性来穿透大脑。在这里，我们通过原始的有机化学过程合成了肌酸脂肪酯。在体外基于大鼠原代细胞的血脑屏障模型和大鼠原代神经元细胞模型上进行的筛选证明，根据结构-活性关系，这些前药的有趣特性可整合到内皮细胞，星形胶质细胞和神经元细胞中。与内源性肌酸含量相比，十二烷基肌酸酯在病理性人类成纤维细胞中的肌酸含量增加了20倍，这表明它可能是一种有前途的候选药物。

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