Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6784-7. doi: 10.1016/j.bmcl.2009.09.081. Epub 2009 Sep 25.

Abstract

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

MeSH terms

  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemical synthesis
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Deoxycytidine Kinase / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Deoxycytidine
  • Deoxycytidine Kinase
  • 5-fluoro-2'-deoxycytidine