1z6e: Difference between revisions
New page: left|200px<br /> <applet load="1z6e" size="450" color="white" frame="true" align="right" spinBox="true" caption="1z6e, resolution 1.8Å" /> '''Crystal Structure of... |
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[[Image:1z6e.gif|left|200px]]<br /> | [[Image:1z6e.gif|left|200px]]<br /><applet load="1z6e" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1z6e, resolution 1.8Å" /> | caption="1z6e, resolution 1.8Å" /> | ||
'''Crystal Structure of Factor Xa complexed to Razaxaban'''<br /> | '''Crystal Structure of Factor Xa complexed to Razaxaban'''<br /> | ||
==Overview== | ==Overview== | ||
Modification of a series of pyrazole factor Xa inhibitors to incorporate | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
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 IK8 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:// | 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]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Alexander, R | [[Category: Alexander, R S.]] | ||
[[Category: Bai, S.]] | [[Category: Bai, S.]] | ||
[[Category: Clark, C | [[Category: Clark, C G.]] | ||
[[Category: Ellis, C | [[Category: Ellis, C D.]] | ||
[[Category: Han, Q.]] | [[Category: Han, Q.]] | ||
[[Category: He, M | [[Category: He, M Y.]] | ||
[[Category: Knabb, R | [[Category: Knabb, R M.]] | ||
[[Category: Lam, P | [[Category: Lam, P Y.S.]] | ||
[[Category: Li, R.]] | [[Category: Li, R.]] | ||
[[Category: Luettgen, J | [[Category: Luettgen, J M.]] | ||
[[Category: Pinto, D | [[Category: Pinto, D J.P.]] | ||
[[Category: Quan, M | [[Category: Quan, M L.]] | ||
[[Category: Sun, J | [[Category: Sun, J H.]] | ||
[[Category: Teleha, C | [[Category: Teleha, C A.]] | ||
[[Category: Wexler, R | [[Category: Wexler, R R.]] | ||
[[Category: Wong, P | [[Category: Wong, P C.]] | ||
[[Category: IK8]] | [[Category: IK8]] | ||
[[Category: coagulation cascade]] | [[Category: coagulation cascade]] | ||
[[Category: factor xa]] | [[Category: factor xa]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:12:29 2008'' | ||
Revision as of 17:12, 21 February 2008
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Crystal Structure of Factor Xa complexed to Razaxaban
OverviewOverview
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).
DiseaseDisease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this StructureAbout this Structure
1Z6E is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.
ReferenceReference
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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