Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor

N-[3-[[[(1S)-4-(5-Amino-2-pyridinyl)-1-[[4-difluoromethylene)-1-piperidinyl] carbonyl] butyl] amino] sulfonyl][1,1'-biphenyl]-2-yl]acetamide hydrochloride (SSR182289A) is a novel, potent, and selective thrombin inhibitor. We have examined the antithrombotic properties of SSR182289A administered by i.v. and p.o. routes in several different animal thrombosis models in comparison with reference antithrombotic agents. Oral administration of SSR182289A produced dose-related antithrombotic effects in the following models; rat venous thrombosis (ED50 0.9 mg/kg p.o.), rat silk thread arterio-venous (AV) shunt (ED50 3.8 mg/kg p.o.), rat thromboplastin-induced AV shunt (ED50 3.1 mg/kg p.o.), rat carotid artery thrombosis (ED200 5.9 mg/kg p.o.), and rabbit venous thrombosis (ED50 7.5 mg/kg p.o.). Administered as an i.v. bolus, SSR182289A showed antithrombotic activity in the above models with ED50/ED200 values in the range of 0.2 to 1.9 mg/kg i.v. SSR182289A increased rat tail transection bleeding time at doses greater than or equal to10 mg/kg p.o. In the rat thromboplastin-induced AV shunt model, SSR182289A 10 mg/kg p.o. produced marked antithrombotic effects at 30, 60, 120, and 240 min after administration. Hence, SSR182289A demonstrates potent oral antithrombotic properties in animal venous, AV-shunt, and arterial thrombosis models.