ABSTRACT
OBJECTIVES: Dabigatran etexilate is the first oral thrombin inhibitor to demonstrate superior efficacy to warfarin for stroke prevention in patients with atrial fibrillation. This study describes the in vitro, ex vivo anticoagulant and in vivo antithrombotic effects of an oral thrombin inhibitor, S35972, in comparison with dabigatran etexilate. METHODS: Enzyme assays with thrombin and related serine proteases were performed. Clotting times, including activated partial thromboplastin time (APTT) and thrombin time (TT), were measured in vitro in different species and ex vivo in dogs and rats to determine pharmacologic bioavailabilities. The formation of occlusive venous and arterial thrombi in the rat vena cava and aorta was induced with stasis plus thromboplastin or ferrous chloride, respectively. RESULTS: S35972 inhibited human thrombin with an IC(50) of 3.7 nm, and did not inhibit other serine proteases. The anticoagulant activities of S35972 in vitro were comparable in dog and human plasmas, and the sensitivity of the clotting times to S35972 was TT > APTT > prothrombin time. In the fasted dog, oral administration of 3 mg kg(-1) S35972 increased TT rapidly and for at least 8 h, and its pharmacologic bioavailability was 75.4% ± 0.1%. In the rat venous thrombosis model, 3 mg kg(-1) oral S35972 or dabigatran etexilate significantly decreased the thrombus weight. In the rat aortic thrombosis model, oral S35972 at 10mg kg(-1) significantly decreased thrombus weight, by approximately 50%, whereas, at this dose, no effect was obtained with dabigatran etexilate. CONCLUSIONS: S35972 is a non-prodrug thrombin inhibitor with high selectivity, oral bioavailability, and antithrombotic efficacy.
Subject(s)
Anticoagulants/pharmacology , Pyrazines/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Benzimidazoles , Biological Availability , Blood Coagulation Tests , Dabigatran , Disease Models, Animal , Dogs , Drug Evaluation , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Thrombosis/drug therapyABSTRACT
Structural variations of P2 and P3 residues in tripeptidic boroarginine thrombin inhibitors led to compounds with similar potency than reference compound DuP 714, but with enhanced selectivity for thrombin compared to plasmin.
