Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa

Bioorg Med Chem Lett. 2005 Jun 15;15(12):3006-11. doi: 10.1016/j.bmcl.2005.04.037.

Abstract

We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzamidines / chemistry*
  • Binding Sites
  • Drug Design*
  • Factor VIIa / antagonists & inhibitors*
  • Factor VIIa / chemistry
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Protein Binding
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Benzamidines
  • Fibrinolytic Agents
  • Pyrazines
  • Serine Proteinase Inhibitors
  • Factor VIIa
  • benzamidine