Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

J Med Chem. 2018 Jun 28;61(12):5245-5256. doi: 10.1021/acs.jmedchem.8b00085. Epub 2018 Jun 14.

Abstract

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Administration, Oral
  • Animals
  • Binding Sites
  • Biological Availability
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Isoenzymes / antagonists & inhibitors
  • Mice, Inbred C57BL
  • Multiple Sclerosis / drug therapy
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phthalimides / chemistry
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Phthalimides
  • phthalimidine
  • Adenosine Triphosphate