Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent

J Med Chem. 2011 Oct 13;54(19):6734-50. doi: 10.1021/jm200629m. Epub 2011 Sep 7.

Abstract

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology
  • Blood Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Hepatocytes / metabolism
  • Humans
  • Kinesin / antagonists & inhibitors*
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Mice, Nude
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / pharmacokinetics
  • Pyrimidinones / pharmacology
  • Rats
  • Rats, Wistar
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Blood Proteins
  • KIF11 protein, human
  • N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide
  • Pyrimidinones
  • Kinesin