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).
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemistry , Anaplastic Lymphoma Kinase , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Computer Simulation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Receptor Protein-Tyrosine Kinases , Structure-Activity RelationshipABSTRACT
The preparation in multigram scale of two metabolites 3-(3,5-dichloro-4-methyl-benzoylamino)-2-hydroxy-3-methyl-pentanoic acid and 3-(3,5-dichloro-benzoylamino)-3-methyl-2-oxo-butyric acid isolated from soil treated with either Zoxium fungicide or Kerb herbicide was efficiently accomplished using a common 5-step synthetic process starting from easily available raw materials.
