PDBsum entry 4bti

Hydrolase

PDB id: 4bti

Contents

Protein chains

54 a.a.

235 a.a.

Ligands

7R9 ×2

Metals

_CA ×2

Waters ×609

PDB id:

4bti

Name:

Hydrolase

Title:

Factor xa in complex with the dual thrombin-fxa inhibitor 58.

Structure:

Coagulation factor x heavy chain. Chain: a, e. Synonym: stuart factor, stuart-prower factor activated factor xa heavy chain. Other_details: des-gla domain. Coagulation factor x light chain. Chain: b, f. Synonym: stuart factor, stuart-prower factor, factor x heavy chain. Ec: 3.4.21.6

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Other_details: isolated from human serum. Other_details: isolated from human serum

Resolution:

2.30Å R-factor: 0.169 R-free: 0.224

Authors:

J.Meneyrol,M.Follmann,G.Lassalle,V.Wehner,G.Barre,T.Rousseaux, J.M.Altenburger,F.Petit,Z.Bocskei,C.Stehlin-Gaon,H.Schreuder,N.Alet, J.-P.Herault,L.Millet,F.Dol,C.Hasbrand,P.Schaeffer,F.Sadoun, S.Klieber,C.Briot,F.Bono,J.-M.Herbert

Key ref:

J.Meneyrol et al. (2013). 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, 9441-9456. PubMed id: 24175584 DOI: 10.1021/jm4005835

Date:

18-Jun-13 Release date: 25-Dec-13

Protein chains

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 54 a.a.

Protein chains

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 235 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, E, F: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

DOI no: 10.1021/jm4005835

J Med Chem 56:9441-9456 (2013)

PubMed id: 24175584

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

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.