4BTU

Factor Xa in complex with the dual thrombin-FXa inhibitor 57.

4BTU の概要

• エントリーDOI: 10.2210/pdb4btu/pdb
• 関連するPDBエントリー: 4BTI 4BTT
• 分子名称: COAGULATION FACTOR X LIGHT CHAIN, COAGULATION FACTOR X HEAVY CHAIN, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, sar107375, factor xa inhibitor, thrombin inhibitor, chlorothiophene p1 fragment, s3 subsite, microsomes stability, oral antithrombotic, dual inhibitor, iv antithrombotic
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 79489.86

構造登録者

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. (登録日: 2013-06-19, 公開日: 2013-12-18, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.37 Å)