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SSR182289A competitively inhibits human thrombin (K i ϭ 0.031 Ϯ 0.002 M) and shows good selectivity with respect to other human proteases, e.g., trypsin (K i ϭ 54 Ϯ 2 M), factor Xa (K i ϭ 167 Ϯ 9 M), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K i values Ͼ250 M). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC 100 thrombin time 96 Ϯ 7 nM) and inhibited tissue factor-induced thrombin generation (IC 50 of 0.15 Ϯ 0.02 M). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC 50 value of 32 Ϯ 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 Ϯ 356%; ecarin clotting time (ECT), 1134 Ϯ 204%; and activated partial thromboplastin time (aPTT), 91 Ϯ 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 Ϯ 425%; ECT, 2017 Ϯ 341%; and aPTT, 113 Ϯ 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.

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Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 μM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 μM) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.