1z6e

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[[Image:1z6e.gif|left|200px]]<br /><applet load="1z6e" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1z6e.gif|left|200px]]
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caption="1z6e, resolution 1.8&Aring;" />
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'''Crystal Structure of Factor Xa complexed to Razaxaban'''<br />
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{{Structure
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|PDB= 1z6e |SIZE=350|CAPTION= <scene name='initialview01'>1z6e</scene>, resolution 1.8&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=IK8:1-(3-AMINO-1,2-BENZISOXAZOL-5-YL)-N-(4-{2-[(DIMETHYLAMINO)METHYL]-1H-IMIDAZOL-1-YL}-2-FLUOROPHENYL)-3-(TRIFLUOROMETHYL)-1H-PYRAZOLE-5-CARBOXAMIDE'>IK8</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6]
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|GENE=
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}}
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'''Crystal Structure of Factor Xa complexed to Razaxaban'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1Z6E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IK8:'>IK8</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z6E OCA].
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1Z6E is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z6E OCA].
==Reference==
==Reference==
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Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor., Quan ML, Lam PY, Han Q, Pinto DJ, He MY, Li R, Ellis CD, Clark CG, Teleha CA, Sun JH, Alexander RS, Bai S, Luettgen JM, Knabb RM, Wong PC, Wexler RR, J Med Chem. 2005 Mar 24;48(6):1729-44. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15771420 15771420]
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Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor., Quan ML, Lam PY, Han Q, Pinto DJ, He MY, Li R, Ellis CD, Clark CG, Teleha CA, Sun JH, Alexander RS, Bai S, Luettgen JM, Knabb RM, Wong PC, Wexler RR, J Med Chem. 2005 Mar 24;48(6):1729-44. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15771420 15771420]
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: factor xa]]
[[Category: factor xa]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:12:29 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:31:41 2008''

Revision as of 13:31, 20 March 2008

Image:1z6e.gif


PDB ID 1z6e

Drag the structure with the mouse to rotate
, resolution 1.8Å
Ligands:
Activity: Coagulation factor Xa, with EC number 3.4.21.6
Coordinates: save as pdb, mmCIF, xml



Crystal Structure of Factor Xa complexed to Razaxaban


Contents

Overview

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimeth ylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

Disease

Known disease associated with this structure: Factor X deficiency OMIM:[227600]

About this Structure

1Z6E is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor., Quan ML, Lam PY, Han Q, Pinto DJ, He MY, Li R, Ellis CD, Clark CG, Teleha CA, Sun JH, Alexander RS, Bai S, Luettgen JM, Knabb RM, Wong PC, Wexler RR, J Med Chem. 2005 Mar 24;48(6):1729-44. PMID:15771420

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