Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.

Abstract Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1′-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1′ group. Over the course of the optimization efforts, the 1-(1 H -tetrazol-5-yl)cyclopropane P1′ substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.