PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor

Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30.

Abstract

A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line, Tumor
  • Humans
  • Mice
  • Mice, Nude
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / pharmacokinetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / pharmacokinetics
  • Tropanes / chemistry
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacokinetics
  • Xenograft Model Antitumor Assays

Substances

  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Triazines
  • Tropanes
  • Urea
  • 1-(4-(4-(3-oxa-8-azabicyclo(3.2.1)octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea
  • Phosphatidylinositol 3-Kinase
  • TOR Serine-Threonine Kinases