Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide (CZC24758), as a potent, orally bioavailable and selective inhibitor of PI3K for the treatment of inflammatory disease

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4613-8. doi: 10.1016/j.bmcl.2012.05.090. Epub 2012 Jun 5.

Abstract

Herein, we disclose the discovery of a series of 7-substituted triazolopyridines which culminated in the identification of 14 (CZC24758), a potent, orally bioavailable small-molecule inhibitor of PI3Kγ, an attractive drug target for inflammatory and autoimmune disorders. Compound 14 has excellent selectivity across the kinome, demonstrates good potency in cell based assays and furthermore exhibits in vivo efficacy in a collagen induced arthritis model in mouse after oral dosing.

MeSH terms

  • Animals
  • Drug Discovery
  • Granulocytes / drug effects
  • Hydrogen Bonding
  • Inflammation / drug therapy
  • Male
  • Mice
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Models, Molecular
  • Molecular Structure
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyridines / chemistry
  • Pyridines / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / therapeutic use
  • Triazoles / chemistry
  • Triazoles / therapeutic use

Substances

  • 5-(2-amino-(1,2,4)triazolo(1,5-a)pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Sulfonamides
  • Triazoles