4LOY: 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)

Citation:
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 muM, 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 muM) 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.
PDB ID: 4LOYDownload
MMDB ID: 120454
PDB Deposition Date: 2013/7/14
Updated in MMDB: 2014/06
Experimental Method:
x-ray diffraction
Resolution: 1.77  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4LOY: trimeric; determined by author and by software (PISA)
Molecular Components in 4LOY
Label Count Molecule
Proteins (3 molecules)
1
Thrombin Heavy Chain(Gene symbol: F2)
Molecule annotation
1
Hirudin Variant-2
Molecule annotation
1
Thrombin Light Chain(Gene symbol: F2)
Molecule annotation
Chemicals (4 molecules)
1
1
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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