Download MendeleySelective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.
Norman, M.H., Andrews, K.L., Bo, Y.Y., Booker, S.K., Caenepeel, S., Cee, V.J., D'Angelo, N.D., Freeman, D.J., Herberich, B.J., Hong, F.T., Jackson, C.L., Jiang, J., Lanman, B.A., Liu, L., McCarter, J.D., Mullady, E.L., Nishimura, N., Pettus, L.H., Reed, A.B., Miguel, T.S., Smith, A.L., Stec, M.M., Tadesse, S., Tasker, A., Aidasani, D., Zhu, X., Subramanian, R., Tamayo, N.A., Wang, L., Whittington, D.A., Wu, B., Wu, T., Wurz, R.P., Yang, K., Zalameda, L., Zhang, N., Hughes, P.E.(2012) J Med Chem 55: 7796-7816
- PubMed: 22897589
- DOI: https://doi.org/10.1021/jm300846z
- Primary Citation of Related Structures:
4FLH - PubMed Abstract:
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.
Organizational Affiliation:
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. [email protected]
