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

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 (p K a ∼ 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.