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Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-06-03 , DOI: 10.1021/acs.jmedchem.0c00463
Irina N Gaisina 1, 2 , Norton P Peet 2 , Letitia Wong 2 , Adam M Schafer 3 , Han Cheng 3 , Manu Anantpadma 4, 5 , Robert A Davey 4, 5 , Gregory R J Thatcher 1 , Lijun Rong 3
Affiliation  

The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds 4150). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.

中文翻译:

发现和结构优化的4-(氨基甲基)苯甲酰胺作为埃博拉和马尔堡病毒感染的强效进入抑制剂。

西非最近爆发的埃博拉疫情突显了对未来埃博拉病毒暴发的有效和实用疗法的强烈需求。我们发现了一系列新的有效的埃博拉病毒进入小分子抑制剂。这些基于4-(氨基甲基)苯甲酰胺的抑制剂也可有效抵抗马尔堡病毒。这些化合物的合成途径可以制备各种各样的结构,包括二氢吲哚的构象受限子集(化合物4150)。化合物20233233,和35是埃博拉(马英嘉)和马尔堡(安哥拉)感染性病毒的优良的抑制剂。代表化合物(203235)在血浆和肝微粒体(大鼠和人)中显示出良好的代谢稳定性,而32没有抑制CYP3A4或CYP2C9。这些4-(氨基甲基)苯甲酰胺适于进一步优化作为丝状病毒进入的抑制剂,并有可能被开发为用于治疗和控制埃博拉病毒感染的治疗剂。
更新日期:2020-07-09
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