Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

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• 作者：Mark H. Norman ; Kristin L. Andrews ; Yunxin Y. Bo ; Shon K. Booker ; Sean Caenepeel ; Victor J. Cee ; Noel D. D鈥橝ngelo ; Daniel J. Freeman ; Bradley J. Herberich ; Fang-Tsao Hong ; Claire L. M. Jackson ; Jian Jiang ; Brian A. Lanman ; Longbin Liu ; John D. McCarter ; Erin L. Mullady ; Nobuko Nishimura ; Liping H. Pettus ; Anthony B. Reed ; Tisha San Miguel ; Adrian L. Smith ; Markian M. Stec ; Seifu Tadesse ; Andrew Tasker ; Divesh Aidasani ; Xiaochun Zhu ; Raju Subramanian ; Nuria A. Tamayo ; Ling Wang ; Douglas A. Whittington ; Bin Wu ; Tian Wu ; Ryan P. Wurz ; Kevin Yang ; Leeanne Zalameda ; Nancy Zhang ; Paul E. Hughes
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7796-7816
• 全文大小：703K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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.