S35972, a direct‐acting thrombin inhibitor with high oral bioavailability and antithrombotic efficacy
| Autor: | Marie-Odile Vallez, P. Mennecier, I. Marx, Philippe Gloanec, T. J. Verbeuren, A. Rupin, G. De Nanteuil |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Pyridines
medicine.drug_class Administration Oral Biological Availability In Vitro Techniques Pharmacology Thrombin time Dabigatran Inhibitory Concentration 50 Dogs Thrombin Antithrombotic medicine Animals Humans Thromboplastin Pyrroles Blood coagulation test medicine.diagnostic_test business.industry Anticoagulant Anticoagulants Thrombosis Hematology Rats Disease Models Animal Pyrazines Drug Evaluation Benzimidazoles Blood Coagulation Tests business circulatory and respiratory physiology Partial thromboplastin time medicine.drug |
| Zdroj: | Journal of Thrombosis and Haemostasis. 9:1375-1382 |
| ISSN: | 1538-7836 |
| DOI: | 10.1111/j.1538-7836.2011.04286.x |
| Popis: | Summary. 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 IC50 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 10 mg 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. |
| Databáze: | OpenAIRE |
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