Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection

Bioorg Med Chem Lett. 2006 Jan 1;16(1):118-22. doi: 10.1016/j.bmcl.2005.09.039. Epub 2005 Oct 10.

Abstract

We describe the identification, SAR, and pharmacology of the src-family selective lck inhibitor A-770041 that prolongs the survival of major histocompatibility mismatched allografts in models of solid organ transplant rejection for greater than 65 days.

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / pharmacology
  • Graft Rejection / prevention & control*
  • Heart Transplantation / methods
  • Humans
  • Immunophenotyping
  • Immunosuppressive Agents / pharmacology*
  • Inhibitory Concentration 50
  • Kinetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Major Histocompatibility Complex
  • Models, Chemical
  • Models, Molecular
  • Pharmaceutical Preparations
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Rats
  • Time Factors
  • Transplantation, Homologous / methods
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • 1-methyl-1H-indole-2-carboxylic acid (4-(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-3-yl)-2-methoxyphenyl)amide
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Pharmaceutical Preparations
  • Pyrazoles
  • Pyrimidines
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • src-Family Kinases