PDBsum entry 4loy

Hydrolase/hydrolase inhibitor

PDB id: 4loy

Contents

Protein chains

250 a.a.

27 a.a.

Ligands

ASP-PHE-GLU-GLU-ILE-PRO-GLU-GLU-TYS-LEU

NAG

6XS

Metals

_NA ×2

Waters ×294

PDB id:

4loy

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure analysis of thrombin in complex with compound d57, 5-chlorothiophene-2-carboxylic acid [(s)-2-[2-methyl-3-(2- oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1- yl)- 3-oxopropyl]amide (sar107375)

Structure:

Thrombin heavy chain. Chain: h. Fragment: unp residues 364-620. Synonym: thrombin heavy chain. Hirudin variant-2. Chain: i. Fragment: unp residues 62-71. Thrombin light chain. Chain: l.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.77Å R-factor: 0.178 R-free: 0.208

Authors:

C.Stehlin-Gaon,Z.Bocskei

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:

14-Jul-13 Release date: 04-Jun-14

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 250 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 27 a.a.

Enzyme reactions

• Enzyme class: Chains H, L: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

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.