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

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 P1 amidine designed to explore additional interactions with the VIIa residues in the so-called ‘S1 side pocket’. A crystal structure of the designed inhibitors demonstrates the ability of the P1 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.

Graphical abstractWe used structure-based design to develop novel TF/VIIa inhibitors containing a P1 side pocket moiety that engages Lys192 and Gly216 as demonstrated in an enzyme/inhibitor X-ray crystal structure.Figure optionsDownload full-size imageDownload as PowerPoint slide