Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1604-7. doi: 10.1016/j.bmcl.2013.01.094. Epub 2013 Jan 30.

Abstract

Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / metabolism
  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Amidines / metabolism
  • Binding Sites
  • Bridged Bicyclo Compounds / chemistry
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Factor VIIa / antagonists & inhibitors*
  • Factor VIIa / metabolism
  • Protein Binding
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry*
  • Pyrazines / metabolism
  • Pyrimidinones / chemistry*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Amidines
  • Bridged Bicyclo Compounds
  • Pyrazines
  • Pyrimidinones
  • Serine Proteinase Inhibitors
  • Factor VIIa