4BTI

factor Xa in complex with the dual thrombin-FXa inhibitor 58.

Summary for 4BTI

• Entry DOI: 10.2210/pdb4bti/pdb
• Related: 4BTT 4BTU
• Descriptor: COAGULATION FACTOR X HEAVY CHAIN, COAGULATION FACTOR X LIGHT CHAIN, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase, sar107375, factor xa inhibitor, thrombin inhibitor, chlorothiophene p1 fragment, s3 subsite, microsomes stability, oral antithrombotic, dual inhibitor, iv antithrombotic
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 4
• Total formula weight: 79545.06

Authors

Meneyrol, J.,Follmann, M.,Lassalle, G.,Wehner, V.,Barre, G.,Rousseaux, T.,Altenburger, J.M.,Petit, F.,Bocskei, Z.,Stehlin-Gaon, C.,Schreuder, H.,Alet, N.,Herault, J.-P.,Millet, L.,Dol, F.,Hasbrand, C.,Schaeffer, P.,Sadoun, F.,Klieber, S.,Briot, C.,Bono, F.,Herbert, J.-M. (deposition date: 2013-06-18, release date: 2013-12-25, Last modification date: 2024-05-01)

Primary citation

Meneyrol, J.,Follmann, M.,Lassalle, G.,Wehner, V.,Barre, G.,Rousseaux, T.,Altenburger, J.,Petit, F.,Bocskei, Z.,Schreuder, H.,Alet, N.,Herault, J.,Millet, L.,Dol, F.,Florian, P.,Schaeffer, P.,Sadoun, F.,Klieber, S.,Briot, C.,Bono, F.,Herbert, J.
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.
J.Med.Chem., 56:9441-, 2013

PubMed 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.

PubMed: 24175584
DOI: 10.1021/JM4005835

Experimental method

X-RAY DIFFRACTION (2.3 Å)