Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6188-94. doi: 10.1016/j.bmcl.2011.07.082. Epub 2011 Aug 12.

Abstract

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.

MeSH terms

  • Administration, Oral
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Arthus Reaction / drug therapy*
  • Crystallography, X-Ray
  • Drug Discovery
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Structure-Activity Relationship
  • Syk Kinase

Substances

  • Aniline Compounds
  • Anti-Inflammatory Agents
  • GSK143
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, rat