Heteroaryl-linked 5-(1H-benzimidazol-1-yl)-2-thiophenecarboxamides: potent inhibitors of polo-like kinase 1 (PLK1) with improved drug-like properties

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4587-92. doi: 10.1016/j.bmcl.2010.06.009. Epub 2010 Jun 8.

Abstract

Potent inhibitors of PLK1 with acceptable solubility, mouse iv clearance, and reduced CYP450 inhibition were identified. Drug-like properties were improved using a heteroaryl ring as a functional handle for manipulation of inhibitors' physiochemical and DMPK properties.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Computer Simulation
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Injections, Intravenous
  • Mice
  • Polo-Like Kinase 1
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Structure-Activity Relationship
  • Thiophenes / chemistry

Substances

  • Amides
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cytochrome P-450 Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Thiophenes
  • Cytochrome P-450 Enzyme System
  • Protein Serine-Threonine Kinases