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.

• Authors: Pancras C Wong, Earl J Crain, Carol A Watson, William A Schumacher
• Journal: Journal of thrombosis and thrombolysis (J Thromb Thrombolysis) Vol. 32 Issue 2 Pg. 129-37 (Aug 2011) ISSN: 1573-742X [Electronic] Netherlands
• PMID: 21614454 (Publication Type: Journal Article)

Chemical References

• Azetidines
• BMS-262084
• Fibrinolytic Agents
• Piperazines
• Factor XIa

Topics

• Animals
• Azetidines (adverse effects, pharmacology)
• Bleeding Time
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Factor XIa (antagonists & inhibitors)
• Fibrinolytic Agents (adverse effects, pharmacology)
• Male
• Piperazines (adverse effects, pharmacology)
• Platelet Activation (drug effects)
• Platelet Function Tests (methods)
• Rabbits
• Venous Thrombosis (blood, drug therapy)