Methanesulfonamido-cyclohexylamine derivatives of 2,4-diaminopyrimidine as potent ALK inhibitors

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3877-80. doi: 10.1016/j.bmcl.2011.05.040. Epub 2011 May 18.

Abstract

The incorporation of R,R-1,2-diaminocyclohexane at C4 in a series of 2,4-diaminopyrimidines led to a number of ALK inhibitors in which optimized activity was achieved by conversion of the 2-amino group into a methanesulfonamide. Tumor growth inhibition was observed when an orally bioavailable analog was evaluated in a Karpas-299 tumor xenograft mouse model.

MeSH terms

  • Administration, Oral
  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cyclohexylamines / administration & dosage
  • Cyclohexylamines / chemical synthesis*
  • Cyclohexylamines / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Infusion Pumps
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cyclohexylamines
  • Enzyme Inhibitors
  • Pyrimidines
  • 2,4-diaminopyrimidine
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases