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

文献类型：期刊论文

作者Dong, Xiaowu1; Zhan, Wenhu1,6; Zhao, Mengting2; Che, Jinxin1; Dai, Xiaoyang2; Wu, Yizhe1; Xu, Lei3; Zhou, Yubo3; Zhao, Yanmei1; Tian, Tian1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-08-08
卷号62期号:15页码:7264-7288
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b00891
通讯作者Weng, Qinjie(wengqinjie@zju.edu.cn) ; Hu, Yongzhou(huyz@zju.edu.cn)
英文摘要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.
WOS关键词BIOLOGICAL EVALUATION ; PRECLINICAL PHARMACOLOGY ; POTENT INHIBITORS ; MOLECULAR DOCKING ; CANCER ; PERIFOSINE ; PATHWAY ; IDENTIFICATION ; ACTIVATION ; AZD5363
资助项目National Natural Science Foundation of China[81673294] ; National Natural Science Foundation of China[81872878] ; National Natural Science Foundation of China[81741172] ; Zhejiang Provincial Natural Science Foundation of China[LGF18H310001] ; Zhejiang Provincial Natural Science Foundation of China[LGF19H310002] ; Health Bureau of Zhejiang Province[2015RCB002] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-007] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-011-023]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000480500600027
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/288953]  
专题新药研究国家重点实验室
通讯作者Weng, Qinjie; Hu, Yongzhou
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, ZJU ENS Joint Lab Med Chem, Hangzhou 310058, Zhejiang, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Inst Pharmacol & Toxicol, Hangzhou 310058, Zhejiang, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
4.Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou 311402, Zhejiang, Peoples R China
5.Zhejiang Prov Peoples Hosp, Dept Pharm, Hangzhou 310014, Zhejiang, Peoples R China
6.Weill Cornell Med, Dept Microbiol & Immunol, 1300 York Ave, New York, NY 10065 USA
推荐引用方式
GB/T 7714		 Dong, Xiaowu,Zhan, Wenhu,Zhao, Mengting,et al. Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(15):7264-7288.
APA Dong, Xiaowu.,Zhan, Wenhu.,Zhao, Mengting.,Che, Jinxin.,Dai, Xiaoyang.,...&Hu, Yongzhou.(2019).Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design.JOURNAL OF MEDICINAL CHEMISTRY,62(15),7264-7288.
MLA Dong, Xiaowu,et al."Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design".JOURNAL OF MEDICINAL CHEMISTRY 62.15(2019):7264-7288.

入库方式： OAI收割

来源：上海药物研究所

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