2-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety

J Med Chem. 2018 Apr 12;61(7):3114-3125. doi: 10.1021/acs.jmedchem.8b00152. Epub 2018 Apr 3.

Abstract

Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.

MeSH terms

  • Aminopyridines / adverse effects
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / pharmacology*
  • Animals
  • Biological Availability
  • Carboxylic Acids / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Drug Discovery
  • Half-Life
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Conformation
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Aminopyridines
  • Carboxylic Acids
  • Cytochrome P-450 CYP3A Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • MAP4K4 protein, human
  • Protein Serine-Threonine Kinases