Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.
Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss.
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DOI：
10.1021/acs.jmedchem.0c01570
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发表时间：
2021-02-25
影响因子：
7.3
通讯作者：
Jung ME
中科院分区：
文献类型：
--
作者：
Liu X;Flores AA;Situ L;Gu W;Ding H;Christofk HR;Lowry WE;Jung ME
本文报道了UK-5099体外和体内新型类似物的合成和评价，用于开发线粒体丙酮酸载体（MPC）抑制剂治疗脱发。通过改变hit化合物的四个位置，即N1位的烷基、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，对其构效关系有了全面的了解。主要的发现是，在N1位置有3,5-二（三氟甲基）苯基的抑制剂比JXL001 （UK-5099）具有更好的活性，可以增加细胞乳酸的产生。此外，类似物JXL069含有一个7-氮杂酚杂环，也被证明具有显著的MPC抑制活性，这进一步增加了药物设计的化学空间。最后，对十几种类似物进行局部处理，对小鼠剃毛后毛发生长有明显促进作用。
Herein we reported 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 ten analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.
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影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
64.5
作者：
Hsu YC;Pasolli HA;Fuchs E
通讯作者：
Fuchs E
影响因子：
4.1
作者：
SHEARMAN, MS;HALESTRAP, AP
通讯作者：
HALESTRAP, AP
影响因子：
64.5
作者：
Fuchs E
通讯作者：
Fuchs E
应用线粒体丙酮酸载体阻断剂 UK5099 在体外 LnCap 前列腺癌细胞中产生代谢重编程和更强的干细胞样特性。
影响因子：
--
作者：
Zhong Y;Li X;Yu D;Li X;Li Y;Long Y;Yuan Y;Ji Z;Zhang M;Wen JG;Nesland JM;Suo Z
通讯作者：
Suo Z