1509935-88-9Relevant academic research and scientific papers
5-chlorothiophene-2-carboxylic acid [(S)-2-[2-Methyl-3-(2-oxopyrrolidin-1- yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor
Meneyrol, Jerome,Follmann, Markus,Lassalle, Gilbert,Wehner, Volkmar,Barre, Guillaume,Rousseaux, Tristan,Altenburger, Jean-Michel,Petit, Frederic,Bocskei, Zsolt,Schreuder, Herman,Alet, Nathalie,Herault, Jean-Pascal,Millet, Laurence,Dol, Frederique,Florian, Peter,Schaeffer, Paul,Sadoun, Freddy,Klieber, Sylvie,Briot, Christophe,Bono, Fran?oise,Herbert, Jean-Marc
, p. 9441 - 9456 (2014/01/06)
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 (IC 50'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.
