A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

Abstract

BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 μM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…Strategies to inhibit FXI are illustrated in Table 2 and include (1) ASOs that reduce hepatic synthesis of the clotting protein 27,33,44 ; (2) monoclonal antibodies that block FXI activation, FXIa activity, or both 25,45,46 ; (3) aptamers that block FXI activation or activity 47,48 ; and (4) small molecules that block the active site of FXIa [49][50][51] or induce allosteric modulation.…”

Is there a need for an alternative in the era of novel anticoagulants?

“…It is well known that factor XI deficiency is not associated with a major bleeding phenotype [19], but clinical evidence also supports the finding that factor XI deficiency is associated with a reduced risk of stroke and deep vein thrombosis [20]. Based on these clinical insights, investigators have studied the effect of inhibiting [21] or lowering factor XI levels [22]. The latter effort is achieved by specific antisense Factor XI oligonucleotides that selectively inhibit factor XI mRNA expression [22,23].…”

Monocyclic &#946;-Lactams: New Structures for New Biological Activities

“…The lead BMS-3543326 (48) was deeply studied as inhibitor of Factor XIa and it was evaluated in vivo on arterial thrombosis and hemostasis in rat and rabbits, as above reported [58]. This new compound has the potential to complement established parenteral anticoagulants [60]. In a recent review, the pharmacology of some new parenteral anticoagulants, the results of clinical studies, the newly planned or ongoing clinical trials with these compounds, and their potential advantages and drawbacks over existing therapies were discussed [61].…”