Design, synthesis and evaluation of FXIIa inhibitors: toward chiral peptidomimetic amidines and guanidines

A great challenge in anticoagulation therapy is to limit thrombosis without
causing bleeding in patients. Anticoagulants have come closer to this goal
but hemorrhage is still reported. Coagulation factors are further investigated
as potential targets to inhibit. Among them, FXIIa, a serine protease,
appears to be promising according to numerous animal studies. Up to now,
inhibitors of FXIIa under development include proteins, peptides and RNAbased
macromolecules. On the contrary, low-molecular-weight inhibitors are
overlooked. Our goal is to synthesize and assess small molecules as
selective inhibitors of FXIIa. A rational approach is adopted on the basis of
previous work in our laboratory and of our hybrid 3D model of FXIIa. Two
chemolibraries, achiral and chiral, are investigated, both designed to fit as
many binding pockets as possible. The main pattern is made up of a triazole
linked to two substituted arenes. In both cases, a guanidine or an amidine
moiety is expected to play a key role via a coulombic interaction with an
aspartate residue. A peptidomimetic hydroxyethylene moiety is
implemented in the chiral chemolibrary and is expected to fill the oxyanion
hole of the active site. The influence of the presence of stereogenic centers
is studied by comparing the inhibitory activity of both chemolibraries. The
syntheses are driven by molecular docking experiments and by in vitro
testing on several coagulation factors. Eventually, the anticoagulation profile
of the most promising compounds is assessed in human plasma.