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Introduction: Acute stroke intervention with antithrombotic agents is limited due to an increased risk of bleeding and a frequent inability to swallow existing oral agents. Preclinical and early clinical data with an antisense oligonucleotide suggest inhibition of Factor XI (FXI) as a means to achieve antithrombotic efficacy with a reduced risk of bleeding. Here we report a preclinical characterization and results from first-in-human studies of BMS-962212, a first in class, direct, reversible, and highly selective IV small molecule inhibitor of FXIa (FXIa Ki = 0.7 nM).Methods: BMS-962212 at 0.001+0.0063 to 0.46+3.1 mg/kg+mg/kg/h or its vehicle were administered IV in anesthetized rabbit models of electrically-induced carotid artery thrombosis and cuticle bleeding time. To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-962212 in humans, 6 healthy subjects per dose panel received BMS-962212 at 1.5, 4, 10, and 25 mg/h as 2 hour IV infusions and, respectively, 1, 3, 9, and 20 mg/h as 5 day IV infusions, randomized with placebo. Additionally, 12 healthy subjects received BMS-962212 at 15 mg/h co-administered with 325 mg ASA for 5 days.Results: In rabbits, BMS-962212 reduced thrombus weight with an EC50 of 80 nM. At a dose that produced 80% antithrombotic efficacy, BMS-962212 did not increase bleeding time. BMS-962212 increased ex vivo activated partial thromboplastin time (aPTT) dose-dependently without changing prothrombin time and thrombin time. In humans, IV administration of BMS-962212 was well tolerated with no serious adverse events observed. Within 30 minutes of BMS-962212 administration, >90% of the mean maximal aPTT within each dose group was achieved. Following completion of the infusion, BMS-962212 demonstrated rapid drug elimination with a direct relationship observed with aPTT decreasing by more than 50% within 4 hours. Template bleeding times were not increased by BMS-962212 alone or when co-administered with ASA.Conclusion: BMS-962212 exhibits properties suited for investigational use as an acute care antithrombotic agent including robust antithrombotic activity with a low potential to increase bleeding risk in preclinical models, and a rapid onset and offset of aPTT activity in humans.