Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

J Med Chem. 2015 Oct 22;58(20):8182-99. doi: 10.1021/acs.jmedchem.5b01072. Epub 2015 Oct 2.

Abstract

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Brain / metabolism*
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics*
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Neurodegenerative Diseases / drug therapy
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Enzyme Inhibitors
  • Pyrimidines
  • MAP Kinase Kinase Kinases
  • mitogen-activated protein kinase kinase kinase 12
  • MAP Kinase Kinase 4

Associated data

  • PDB/5CEN
  • PDB/5CEO
  • PDB/5CEP
  • PDB/5CEQ