Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease

J Med Chem. 2016 Aug 11;59(15):7239-51. doi: 10.1021/acs.jmedchem.6b00799. Epub 2016 Jul 27.


A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Biological Availability
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Dose-Response Relationship, Drug
  • Male
  • Models, Molecular
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Tract Diseases / drug therapy*
  • Respiratory Tract Diseases / metabolism
  • Structure-Activity Relationship


  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Class Ia Phosphatidylinositol 3-Kinase