Discovery of phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance

Bioorg Med Chem Lett. 2012 Nov 1;22(21):6671-6. doi: 10.1016/j.bmcl.2012.08.102. Epub 2012 Sep 6.

Abstract

Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110β isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors*
  • Animals
  • Bleeding Time
  • Blood Platelets / drug effects*
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Dogs
  • Drug Discovery*
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology*
  • Inhibitory Concentration 50
  • Insulin Resistance
  • Molecular Structure
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Protein Isoforms / antagonists & inhibitors*
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Rats

Substances

  • 4-(2-hydroxyethyl(1-naphthylmethyl)amino)-6-((2S)-2-methylmorpholin-4-yl)-1Hpyrimidin-2-one
  • Fibrinolytic Agents
  • Morpholines
  • Protein Isoforms
  • Pyrimidinones
  • Class I Phosphatidylinositol 3-Kinases
  • p110delta protein, rat
  • 1-Phosphatidylinositol 4-Kinase