Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents

Bioorg Med Chem. 2016 Jul 1;24(13):2897-2906. doi: 10.1016/j.bmc.2016.04.060. Epub 2016 Apr 28.

Abstract

Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity.

Keywords: Cancer; Molecular planarity; PI3K; Pharmacokinetic profile; SBDD; Solubility.

MeSH terms

  • Animals
  • Enzyme Activation / drug effects
  • Heterografts
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Solubility
  • Water / chemistry*

Substances

  • Phenylurea Compounds
  • Phosphoinositide-3 Kinase Inhibitors
  • Water