Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa

Bioorg Med Chem Lett. 2007 Aug 15;17(16):4568-74. doi: 10.1016/j.bmcl.2007.05.090. Epub 2007 Jun 6.

Abstract

Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem.2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa approximately 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.

MeSH terms

  • Anticoagulants / chemistry*
  • Anticoagulants / pharmacology*
  • Drug Design
  • Factor VIIa / antagonists & inhibitors*
  • Molecular Structure
  • Pyrans / chemistry*
  • Pyrans / pharmacology*
  • Structure-Activity Relationship
  • Thromboplastin / antagonists & inhibitors*

Substances

  • Anticoagulants
  • Pyrans
  • Thromboplastin
  • Factor VIIa