Phosphoinositide-3-kinase inhibitors: Evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511

Abstract 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 EC 50 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.