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首页> 外文期刊>Journal of Medicinal Chemistry >Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss
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Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss

机译：开发新型线粒体丙酮酸载体抑制剂治疗脱发

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Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both in vitro and in vivo for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure–activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than JXL001 (UK-5099) to increase cellular lactate production. Additionally, analogue JXL069 , possessing a 7-azaindole heterocycle, was also shown to have significant MPC inhibition activity, which further increases the chemical space for drug design. Finally, more than 10 analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.
机译：在此，我们报告了UK-5099新型类似物的合成和评价，这些类似物在体外和体内均，用于开发治疗脱发的线粒体丙酮酸载体（MPC）抑制剂。通过改变hit化合物的四个位置，即N1位置上的烷基、吲哚核上的取代基、各种芳香族和杂芳香族核结构以及各种Michael受体，可以全面理解结构-活性关系。主要发现是，在N1位置带有3,5-双（三氟甲基）苄基的抑制剂在增加细胞乳酸生成方面比JXL001（UK-5099）具有更好的活性。此外，具有7-氮杂吲哚杂环的类似物JXL069也显示出显著的MPC抑制活性，这进一步增加了药物设计的化学空间。最后，通过局部治疗在剃光的小鼠上测试了10多种类似物，并促进了小鼠的毛发生长。

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