5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.
5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.
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5-氟咪唑并[4,5-b]吡啶是一种特权片段，可为有效的锥虫甲硫氨酰-tRNA 合成酶抑制剂提供生物利用度。
DOI：
10.1021/acsinfecdis.6b00036
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发表时间：
2016
影响因子：
5.3
通讯作者：
Fan,Erkang
中科院分区：
文献类型：
--
作者：
Zhang,Zhongsheng;Koh,ChoYeow;Ranade,RanaeM;Shibata,Sayaka;Gillespie,JRobert;Hulverson,MatthewA;Huang,Wenlin;Nguyen,Jasmine;Pendem,Nagendar;Gelb,MichaelH;Verlinde,ChristopheLMJ;Hol,WimGJ;Buckner,FrederickS;Fan,Erkang
氟化是提高药物分子生物利用度的众所周知的策略。然而，其对疗效的影响并不容易预测。在此基础上，我们发现了布氏锥虫甲硫氨酰-tRNA合成酶抑制剂的一个有利的靶点。特别地，将5-氟咪唑并[4，5-B]吡啶掺入抑制剂中导致中枢神经系统生物利用度和维持或甚至改善的功效。
Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase ofTrypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.