Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease

J Med Chem. 2015 Jan 8;58(1):480-511. doi: 10.1021/jm501624r. Epub 2014 Dec 3.

Abstract

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

MeSH terms

  • Adenosine / chemistry
  • Adenosine / metabolism
  • Adenosine / pharmacology*
  • Animals
  • Autoimmune Diseases / prevention & control*
  • Cells, Cultured
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / chemistry
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Discovery
  • Female
  • Humans
  • Inflammation / prevention & control*
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology*
  • Rats, Inbred Lew
  • Sf9 Cells
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human
  • Adenosine

Associated data

  • PDB/4WWN
  • PDB/4WWO
  • PDB/4WWP