Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
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通过构象限制和基于结构的设计发现 3,4,6-三取代哌啶衍生物作为口服活性、低 hERG 阻断 Akt 抑制剂
DOI：
10.1021/acs.jmedchem.9b00891
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发表时间：
2019-08-08
影响因子：
7.3
通讯作者：
Hu, Yongzhou
中科院分区：
文献类型：
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作者：
Dong, Xiaowu;Zhan, Wenhu;Hu, Yongzhou
基于构象限制策略和先导化合物Al 2，合成了一系列3，4-二取代哌啶衍生物，其在体内外均表现出较强的抗肿瘤活性，但明显的安全性问题限制了其进一步开发。因此，系统地探索化合物A1 2的结构活性关系，包括苯基、铰链键和哌啶部分，导致发现了优异的上级3，4，6-三取代哌啶衍生物E22。E22在Aktl和癌细胞抑制中显示出增加的效力，显着减少了人类ether-a-go-go相关的基因阻断，并显着改善了安全性。化合物E22还表现出良好的激酶选择性，具有良好的药代动力学特征，并显示出非常有效的体内抗肿瘤功效，在SKOV 3异种移植模型中具有超过90%的肿瘤生长抑制。进行进一步的机制研究以证明化合物E22可以显著抑制来自异种移植模型的细胞和肿瘤组织中Akt激酶下游的蛋白质的磷酸化。
A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, Al2, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure activity relationship of compound Al2, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Aktl and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.