Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma

J Med Chem. 2006 Jun 29;49(13):3857-71. doi: 10.1021/jm0601598.

Abstract

Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethylene thiazolidinediones as selective, ATP-competitive PI3Kgamma inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kgamma identified key pharmacophore features for potency and selectivity. An acidic NH group on the thiazolidinedione moiety and a hydroxy group on the furan-2-yl-phenyl part of the molecule play crucial roles in binding to PI3K and contribute to class IB PI3K selectivity. Compound 26 (AS-252424), a potent and selective small-molecule PI3Kgamma inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects. Oral administration of 26 in a mouse model of acute peritonitis led to a significant reduction of leukocyte recruitment.

MeSH terms

  • Acute Disease
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / physiology
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Class Ib Phosphatidylinositol 3-Kinase
  • Crystallography, X-Ray
  • Furans / chemical synthesis*
  • Furans / chemistry
  • Furans / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Mast Cells / drug effects
  • Mast Cells / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Monocytes / drug effects
  • Monocytes / physiology
  • Neutrophils / immunology
  • Peritonitis / chemically induced
  • Peritonitis / drug therapy
  • Peritonitis / immunology
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis*
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology
  • Thioglycolates

Substances

  • 5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione
  • Furans
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Thiazolidinediones
  • Thioglycolates
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Proto-Oncogene Proteins c-akt