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

Abstract

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 K = 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.

Identifying new clotting factor XIa inhibitors in virtual high‐throughput screens using PCA‐GA‐SVM models and signature

“…Researchers have been targeting Factor XI for inhibition since the 1970s, starting with four protease inhibitors: α1protease inhibitor, 18 antithrombin III, 19 C1-inhibitor, 20 and α2plasmid inhibitor. 21 Since then, derivatives of the original protease inhibitors 22 and other kinds of inhibitors [23][24][25][26][27][28][29] have been developed. To maximize the likelihood of developing a safe antithrombosis treatment, other techniques should be utilized to supplement traditional discovery methods.…”

Recent advances in the discovery and development of factor XI/XIa inhibitors

“…Very recently, Pinto et al. reported a new series of active site inhibitors of human FXIa in which the central phenylalanine domain of inhibitor 26 was replaced with either substituted pyrrolidine (inhibitor 44 ), THIQ‐3‐carboxylate (inhibitor 45 ), or THIQ‐1‐carboxylate (inhibitor 46 ; Figure ) . Inhibitor 44 showed a modest potency with a FXIa K i value of 23 nM and APTT EC 1.5 x value of 36 μM.…”

“…Inhibitor 44 showed a modest potency with a FXIa K i value of 23 nM and APTT EC 1.5 x value of 36 μM. The two homochiral THIQ derivatives exhibited weaker potency (inhibitor 45 ) or better potency (inhibitor 46 ) with FXIa K i values of 1.7 μM and 11 nM, respectively . Attempts aimed at enhancing the potency of inhibitor 46 by replacing the THIQ‐1‐carboxylate moiety, which points to S1ʹ subsite in the active site of FXIa, with a host of bicyclic heteroaromatic systems failed.…”

“…This molecule inhibited human plasma kallikrein and chymotrypsin with K i values of 0.31 and 11 μM, respectively. Furthermore, inhibitor 49 demonstrated no cytochrome inhibition activity ( IC 50 values > 40 μM), was stable in dog, rat, and human liver microsomes ( T 0.5 = 120, 59, and 108 min, respectively), and was Ames test negative, which suggested acceptable pharmaceutical properties considering the primary goal of the program …”

“…117 In these models, inhibitor 39 or vehicle was intravenously administered before the induction of Figure 13). 119 Inhibitor 44 showed a modest potency with a FXIa To determine the antithrombotic efficacy of this molecule in animal models, the rabbit AV shunt thrombosis model was used. 120,121 Using a dose protocol of 0.23 mg/kg (IV bolus) + 1.55 mg/kg/hr (IV infusion), inhibitor 49 exhibited about 83% inhibition of thrombus formation and increased the APTT up to 1.8-fold with no effect on the PT.…”