Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase

Bioorg Med Chem. 2010 Jun 15;18(12):4351-62. doi: 10.1016/j.bmc.2010.04.087. Epub 2010 Apr 29.

Abstract

Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, and kinase selective analogs were identified that inhibit ALK with IC(50) values approximately 10 nM (enzyme) and approximately 150 nM (cell).

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Computer Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology
  • Receptor Protein-Tyrosine Kinases
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazines
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases