title: 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.
abstract: 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.
authors.affiliation: Sanofi-Aventis R&D , 195 Route d'Espagne, 31036 Toulouse Cedex, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Meneyrol
authors.forename: Markus
authors.initials: M
authors.lastname: Follmann
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lassalle
authors.forename: Volkmar
authors.initials: V
authors.lastname: Wehner
authors.forename: Guillaume
authors.initials: G
authors.lastname: Barre
authors.forename: Tristan
authors.initials: T
authors.lastname: Rousseaux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Altenburger
authors.forename: Frederic
authors.initials: F
authors.lastname: Petit
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bocskei
authors.forename: Herman
authors.initials: H
authors.lastname: Schreuder
authors.forename: Nathalie
authors.initials: N
authors.lastname: Alet
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Herault
authors.forename: Laurence
authors.initials: L
authors.lastname: Millet
authors.forename: Frederique
authors.initials: F
authors.lastname: Dol
authors.forename: Peter
authors.initials: P
authors.lastname: Florian
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Freddy
authors.initials: F
authors.lastname: Sadoun
authors.forename: Sylvie
authors.initials: S
authors.lastname: Klieber
authors.forename: Christophe
authors.initials: C
authors.lastname: Briot
authors.forename: Françoise
authors.initials: F
authors.lastname: Bono
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*; D020246:Venous Thrombosis / Q000188:drug therapy
chemical_list: C586739:5-chlorothiophene-2-carboxylic acid (2-(2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino)-3-(4-methylpiperazin-1-yl)-3-oxopropyl)amide; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010879:Piperazines; D013449:Sulfonamides; D013917:Thrombin