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

The design, synthesis, and biological evaluation of 20 compounds with novel P1 needles is reported. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa∼12), with the goal of the effort an orally bioavailable TF/VIIa inhibitor. 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∼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.