Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
| Autor: | Zegao Jin, Bo Yang, Qinjie Weng, Yongzhou Hu, Qiaojun He, Yubo Zhou, Gang Cheng, Mengting Zhao, Yanmei Zhao, Wenhu Zhan, Jia Li, Jinxin Che, Xiaoyang Dai, Tian Tian, Yizhe Wu, Yanfei Shao, Lei Xu, Xiaowu Dong |
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| Rok vydání: | 2019 |
| Předmět: |
ERG1 Potassium Channel
Protein Conformation hERG Administration Oral Mice Nude Pharmacology 01 natural sciences Rats Sprague-Dawley Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Piperidines In vivo Cell Line Tumor Drug Discovery Human Umbilical Vein Endothelial Cells Animals Humans Structure–activity relationship 030304 developmental biology Mice Inbred BALB C Mice Inbred ICR 0303 health sciences biology Kinase HCT116 Cells Xenograft Model Antitumor Assays In vitro Protein Structure Tertiary Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry biology.protein Molecular Medicine Phosphorylation Piperidine Proto-Oncogene Proteins c-akt Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 62:7264-7288 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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