View source for 4btu


==Factor Xa in complex with the dual thrombin-FXa inhibitor 57.==
<StructureSection load='4btu' size='340' side='right'caption='[[4btu]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4btu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BTU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BTU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.37&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XS:5-CHLORO-THIOPHENE-2-CARBOXYLIC+ACID+[(S)-2-[2-CHLORO-5-FLUORO-3-(2-OXO-PIPERIDIN-1-YL)-BENZENESULFONYLAMINO]-3-(4-METHYL-PIPERAZIN-1-YL)-3-OXO-PROPYL]-AMIDE'>6XS</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4btu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4btu OCA], [https://pdbe.org/4btu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4btu RCSB], [https://www.ebi.ac.uk/pdbsum/4btu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4btu ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[https://omim.org/entry/227600 227600]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.<ref>PMID:2790181</ref> <ref>PMID:1973167</ref> <ref>PMID:1985698</ref> <ref>PMID:7669671</ref> <ref>PMID:8529633</ref> <ref>PMID:7860069</ref> <ref>PMID:8845463</ref> <ref>PMID:8910490</ref> <ref>PMID:10468877</ref> <ref>PMID:10746568</ref> <ref>PMID:10739379</ref> <ref>PMID:11248282</ref> <ref>PMID:11728527</ref> <ref>PMID:12945883</ref> <ref>PMID:15650540</ref> <ref>PMID:17393015</ref> <ref>PMID:19135706</ref> 
== Function ==
[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

5-Chlorothiophene-2-carboxylic Acid [(S)-2-[2-Methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperaz in-1-yl)-3-oxopropyl]amide (SAR107375), a Selective and Potent Orally Active Dual Thrombin and Factor Xa Inhibitor.,Meneyrol J, Follmann M, Lassalle G, Wehner V, Barre G, Rousseaux T, Altenburger JM, Petit F, Bocskei Z, Schreuder H, Alet N, Herault JP, Millet L, Dol F, Florian P, Schaeffer P, Sadoun F, Klieber S, Briot C, Bono F, Herbert JM J Med Chem. 2013 Dec 3. PMID:24175584<ref>PMID:24175584</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4btu" style="background-color:#fffaf0;"></div>

==See Also==
*[[Factor Xa|Factor Xa]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Alet N]]
[[Category: Altenburger JM]]
[[Category: Barre G]]
[[Category: Bocskei Z]]
[[Category: Bono F]]
[[Category: Briot C]]
[[Category: Dol F]]
[[Category: Follmann M]]
[[Category: Hasbrand C]]
[[Category: Herault J-P]]
[[Category: Herbert J-M]]
[[Category: Klieber S]]
[[Category: Lassalle G]]
[[Category: Meneyrol J]]
[[Category: Millet L]]
[[Category: Petit F]]
[[Category: Rousseaux T]]
[[Category: Sadoun F]]
[[Category: Schaeffer P]]
[[Category: Schreuder H]]
[[Category: Stehlin-Gaon C]]
[[Category: Wehner V]]