Potent small molecule inhibitors of spleen tyrosine kinase (Syk)

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3111-4. doi: 10.1016/s0960-894x(03)00658-9.

Abstract

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

MeSH terms

  • Animals
  • Basophils / drug effects
  • Cell Degranulation / drug effects
  • Cell Line
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Precursors / antagonists & inhibitors*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins
  • Oxyquinoline / chemistry
  • Oxyquinoline / pharmacology
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Syk Kinase

Substances

  • Enzyme Inhibitors
  • Enzyme Precursors
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • Oxyquinoline
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, rat