Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)

Previously disclosed
TAFIa inhibitors having a urea zinc-binding
motif were used as the starting point for the development of a novel
class of highly potent inhibitors having a sulfamide zinc-binding
motif. High-resolution X-ray cocrystal structures were used to optimize
the structures and reveal a highly unusual sulfamide configuration.
A selected sulfamide was profiled in vitro and in vivo and displayed
a promising ADMET profile.