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

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5630-5634. doi: 10.1016/j.bmcl.2014.10.085. Epub 2014 Nov 1.

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 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.

Keywords: Kinase inhibitor; Ligand efficiency; Phosphoinositide-3-kinase-alpha; Protein kinase B; Ribose pocket.

MeSH terms

  • Alcohols / chemistry*
  • Animals
  • Female
  • Half-Life
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Molecular Conformation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperazine
  • Piperazines / chemistry*
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacokinetics
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Triazines / chemical synthesis*
  • Triazines / metabolism
  • Triazines / pharmacokinetics

Substances

  • 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
  • AMG 511
  • Alcohols
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Sulfonamides
  • Triazines
  • Piperazine
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases