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J Med Chem. 2012 Sep 13;55(17):7796-816. doi: 10.1021/jm300846z. Epub 2012 Aug 30.

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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Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.

Erratum in

  • J Med Chem. 2012 Oct 25;55(20):8975.


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.

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