Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)

Factor XIa (FXIa)
is a blood coagulation enzyme that is involved
in the amplification of thrombin generation. Mounting evidence suggests
that direct inhibition of FXIa can block pathologic thrombus formation
while preserving normal hemostasis. Preclinical studies using a variety
of approaches to reduce FXIa activity, including direct inhibitors
of FXIa, have demonstrated good antithrombotic efficacy without increasing
bleeding. On the basis of this potential, we targeted our efforts
at identifying potent inhibitors of FXIa with a focus on discovering
an acute antithrombotic agent for use in a hospital setting. Herein
we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent
preclinical efficacy in thrombosis models and aqueous solubility suitable
for intravenous administration. BMS-962212 is a reversible, direct,
and highly selective small molecule inhibitor of FXIa.