1253577-57-9Relevant academic research and scientific papers
Selective class i phosphoinositide 3-kinase inhibitors: Optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511
Norman, Mark H.,Andrews, Kristin L.,Bo, Yunxin Y.,Booker, Shon K.,Caenepeel, Sean,Cee, Victor J.,D'Angelo, Noel D.,Freeman, Daniel J.,Herberich, Bradley J.,Hong, Fang-Tsao,Jackson, Claire L. M.,Jiang, Jian,Lanman, Brian A.,Liu, Longbin,McCarter, John D.,Mullady, Erin L.,Nishimura, Nobuko,Pettus, Liping H.,Reed, Anthony B.,Miguel, Tisha San,Smith, Adrian L.,Stec, Markian M.,Tadesse, Seifu,Tasker, Andrew,Aidasani, Divesh,Zhu, Xiaochun,Subramanian, Raju,Tamayo, Nuria A.,Wang, Ling,Whittington, Douglas A.,Wu, Bin,Wu, Tian,Wurz, Ryan P.,Yang, Kevin,Zalameda, Leeanne,Zhang, Nancy,Hughes, Paul E.
, p. 7796 - 7816 (2012)
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.
Phosphoinositide-3-kinase inhibitors: Evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511
Lanman, Brian A.,Reed, Anthony B.,Cee, Victor J.,Hong, Fang-Tsao,Pettus, Liping H.,Wurz, Ryan P.,Andrews, Kristin L.,Jiang, Jian,McCarter, John D.,Mullady, Erin L.,San Miguel, Tisha,Subramanian, Raju,Wang, Ling,Whittington, Douglas A.,Wu, Tian,Zalameda, Leeanne,Zhang, Nancy,Tasker, Andrew S.,Hughes, Paul E.,Norman, Mark H.
supporting information, p. 5630 - 5634 (2015/01/08)
Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.
