Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

A novel series of macrocyclic FXIa
inhibitors was designed based
on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles,
which were double-digit nanomolar FXIa inhibitors, were further optimized
with assistance from utilization of structure-based drug design and
ligand bound X-ray crystal structures. This effort resulted in the
discovery of a macrocyclic amide linker which was found to form a
key hydrogen bond with the carbonyl of Leu41 in the FXIa active site,
resulting in potent FXIa inhibitors. The macrocyclic FXIa series,
exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in
vitro clotting assay (aPTT EC1.5x = 0.27 μM) and
excellent selectivity against the relevant blood coagulation enzymes.