Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, 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 A12, 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 Akt1 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.本研究基于构象限制策略，以展现出强效体外与体内抗肿瘤活性，但存在明显安全性问题、制约其进一步开发的先导化合物A12为起点，合成得到一系列3,4-二取代哌啶衍生物。随后，研究团队针对化合物A12的苯基、铰链连接区及哌啶环结构位点开展系统构效关系研究，最终获得了性能更优异的3,4,6-三取代哌啶衍生物E22。E22对Akt1及癌细胞的抑制活性显著增强，对人类ether-à-go-go相关基因（human ether-a-go-go-related gene，hERG）的通道阻滞作用大幅降低，安全性得到显著改善。该化合物同时具备良好的激酶选择性与药代动力学特性，体内抗肿瘤活性极强，在SKOV3异种移植模型中肿瘤生长抑制率超过90%。后续机制研究证实，化合物E22可显著抑制细胞及异种移植模型肿瘤组织中Akt激酶下游蛋白的磷酸化水平。