Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability

Bioorg Med Chem. 2015 Dec 15;23(24):7650-60. doi: 10.1016/j.bmc.2015.11.009. Epub 2015 Nov 11.

Abstract

Phosphoinositide 3-kinase (PI3K) is activated in various human cancer cells and well known as a cancer therapy target. We previously reported a dihydropyrrolopyrimidine derivative as a highly potent PI3K inhibitor that has strong tumor growth inhibition in a xenograft model. In this report, we describe further optimization to improve its bioavailability.

Keywords: Cancer; Liver microsomal stability; Molecular planarity; PI3K; Permeability; Pharmacokinetic profile; Solubility.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mice, Inbred BALB C
  • Microsomes, Liver / metabolism
  • Permeability
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics*
  • Pyrroles / administration & dosage
  • Pyrroles / chemistry*
  • Pyrroles / metabolism
  • Pyrroles / pharmacokinetics*
  • Solubility

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • pyrrolopyrimidine