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Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-14 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00283
Ryo Mizojiri 1 , Daisuke Nakata 1 , Yoshihiko Satoh 1 , Daisuke Morishita 1 , Sachio Shibata 1 , Misa Iwatani-Yoshihara 1 , Yohei Kosugi 1 , Mai Kosaka 1 , Junpei Takeda 1 , Shigekazu Sasaki 1 , Kazuaki Takami 1 , Koichiro Fukuda 1 , Masahiro Kamaura 1 , Shinobu Sasaki 1 , Ryosuke Arai 1 , Douglas R. Cary 1 , Yasuhiro Imaeda 1
Affiliation  

Starting from our previous eIF4A3-selective inhibitor 1a, a novel series of (piperazine-1-carbonyl)pyridin-2(1H)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds 1o and 1q showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds 1o and 1q showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.

中文翻译:

新型5-(哌嗪-1-羰基)吡啶-2(1 H)-one衍生物作为口服eIF4A3选择性抑制剂的发现

从我们先前的eIF4A3选择性抑制剂1a开始,设计,合成并评估了一系列新的(哌嗪-1-羰基)吡啶2-2 (1 H)-one衍生物,以鉴定口服生物可利用的探针分子。化合物1o1q表现出改善的理化和ADMET谱,同时保持了有效的和亚型选择性的eIF4A3抑制能力。化合物1o1q与它们有希望的PK曲线和最初的体内PD研究结果相符显示出抗肿瘤功效,T / C值分别为54%和29%,而没有严重的体重减轻。因此,我们的新型化合物代表了对选择性eIF4A3抑制作用进行体内药理研究的有前途的探针分子。
更新日期:2017-09-14
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