1z6e

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[[Image:1z6e.gif|left|200px]]
[[Image:1z6e.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1z6e |SIZE=350|CAPTION= <scene name='initialview01'>1z6e</scene>, resolution 1.8&Aring;
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The line below this paragraph, containing "STRUCTURE_1z6e", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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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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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_1z6e| PDB=1z6e | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1z6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z6e OCA], [http://www.ebi.ac.uk/pdbsum/1z6e PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1z6e RCSB]</span>
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}}
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'''Crystal Structure of Factor Xa complexed to Razaxaban'''
'''Crystal Structure of Factor Xa complexed to Razaxaban'''
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[[Category: Wexler, R R.]]
[[Category: Wexler, R R.]]
[[Category: Wong, P C.]]
[[Category: Wong, P C.]]
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[[Category: coagulation cascade]]
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[[Category: Coagulation cascade]]
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[[Category: factor xa]]
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[[Category: Factor xa]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 17:13:43 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:29:51 2008''
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Revision as of 14:13, 3 May 2008

Image:1z6e.gif

Template:STRUCTURE 1z6e

Crystal Structure of Factor Xa complexed to Razaxaban


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).

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 Page seeded by OCA on Sat May 3 17:13:43 2008

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