Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511
| Autor: | Bradley J. Herberich, Tian Wu, Paul E. Hughes, Claire L. M. Jackson, Nobuko Nishimura, Nancy Zhang, Ryan Wurz, Douglas A. Whittington, Shon Booker, Sean Caenepeel, Tisha San Miguel, Jian Jiang, Anthony B. Reed, Adrian L. Smith, Seifu Tadesse, Brian A. Lanman, Andrew Tasker, Erin L. Mullady, John D. McCarter, Fang-Tsao Hong, Liping H. Pettus, Divesh Aidasani, Victor J. Cee, Ling Wang, Bin Wu, Mark H. Norman, Daniel J. Freeman, Kevin Yang, Longbin Liu, Leeanne Zalameda, Yunxin Y. Bo, Xiaochun Zhu, Kristin L. Andrews, Markian Stec, Nuria A. Tamayo, Raju Subramanian, Noel D'angelo |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Phosphoinositide 3-kinase biology Triazines Chemistry Cell growth Pharmacology Crystallography X-Ray medicine.disease chemistry.chemical_compound In vivo Glioma Drug Discovery Second messenger system medicine biology.protein Molecular Medicine Phosphorylation Phosphatidylinositol Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 55:7796-7816 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511. |
| Databáze: | OpenAIRE |
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