The optimization of aminooxadiazoles as orally active inhibitors of Cdc7

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6396-400. doi: 10.1016/j.bmcl.2013.09.055. Epub 2013 Sep 25.

Abstract

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 μM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.

Keywords: Azaindole; Cancer; Cdc7; Kinase inhibitor; MCM2.

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Oxadiazoles
  • Protein Kinase Inhibitors
  • CDC7 protein, human
  • Protein Serine-Threonine Kinases