Pyrimidinopyrimidine inhibitors of ketohexokinase: exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5326-9. doi: 10.1016/j.bmcl.2012.06.008. Epub 2012 Jun 17.

Abstract

Inhibitors of ketohexokinase (KHK) have potential for the treatment of diabetes and obesity. We have continued studies on a pyrimidinopyrimidine series of potent KHK inhibitors by exploring the 2-position substituent (R(3)) that interacts with Asp-27B in the ATP-binding region of KHK (viz. 1, 2; Table 1). We found that increased spacing between the terminal ammonium group and the heterocyclic scaffold (viz. 16-20), such that interaction with Asp-27B is not possible, still results in potent KHK inhibition (IC(50)=15-50 nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Fructokinases / antagonists & inhibitors*
  • Fructokinases / metabolism
  • Hep G2 Cells
  • Humans
  • Ligands*
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism

Substances

  • Enzyme Inhibitors
  • Ligands
  • Pyrimidines
  • Fructokinases
  • ketohexokinase
  • pyrimidine