Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kδ inhibitors

Bioorg Med Chem Lett. 2017 Feb 1;27(3):679-687. doi: 10.1016/j.bmcl.2016.11.004. Epub 2016 Nov 2.

Abstract

A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC50⩽1nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20-120nM.

Keywords: Aminopyrazine; Inflammation; PI3Kδ inhibitor; Phosphoinositide 3-kinase.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Crystallography, X-Ray
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Pyrazines / chemistry*
  • Pyrazines / metabolism
  • Pyrazines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Protein Isoforms
  • Pyrazines
  • Triazoles
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human