Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

Bioorg Med Chem Lett. 2017 Feb 15;27(4):855-861. doi: 10.1016/j.bmcl.2017.01.016. Epub 2017 Jan 10.

Abstract

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.

Keywords: 7-Phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine; Autoimmune diseases; PI3Kδ; Phosphoinositide 3-kinases; Rheumatoid arthritis.

MeSH terms

  • Amines / chemistry*
  • Amines / metabolism
  • Amines / therapeutic use
  • Animals
  • Autoimmune Diseases / drug therapy
  • Binding Sites
  • Class I Phosphatidylinositol 3-Kinases
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Piperazine
  • Piperazines / chemistry
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use
  • Structure-Activity Relationship
  • Triazines / chemistry

Substances

  • Amines
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Triazines
  • Piperazine
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3cd protein, mouse