Novel 2,3,4,5-tetrahydro-benzo[d]azepine derivatives of 2,4-diaminopyrimidine, selective and orally bioavailable ALK inhibitors with antitumor efficacy in ALCL mouse models

Bioorg Med Chem Lett. 2011 Jan 1;21(1):463-6. doi: 10.1016/j.bmcl.2010.10.115. Epub 2010 Oct 27.

Abstract

The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.

MeSH terms

  • Administration, Oral
  • Anaplastic Lymphoma Kinase
  • Animals
  • Benzazepines / chemistry*
  • Benzazepines / pharmacokinetics
  • Benzazepines / therapeutic use
  • Lymphoma, Large-Cell, Anaplastic / drug therapy*
  • Mice
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases
  • Xenograft Model Antitumor Assays

Substances

  • Benzazepines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • 2,4-diaminopyrimidine
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases