Optimization of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines to generate a highly selective PI3Kδ inhibitor

Bioorg Med Chem. 2019 Mar 15;27(6):1056-1064. doi: 10.1016/j.bmc.2019.02.001. Epub 2019 Feb 1.

Abstract

Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.

Keywords: 5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidine; Isoform selectivity; PI3Kδ inhibitor.

MeSH terms

  • Animals
  • Cells, Cultured
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Molecular Docking Simulation
  • Phosphoinositide-3 Kinase Inhibitors / chemistry*
  • Phosphoinositide-3 Kinase Inhibitors / pharmacokinetics
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology*
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrrolidines
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human