Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa K_i was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.