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...
 
No edit summary
Line 1: Line 1:
[[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"  
<applet load="1z6e" size="450" color="white" frame="true" align="right" spinBox="true"  
caption="1z6e, resolution 1.8&Aring;" />
caption="1z6e, resolution 1.8&Aring;" />
'''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, 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).
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==
Line 11: Line 10:


==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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Z6E OCA].  
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==
Line 18: Line 17:
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: Alexander, R.S.]]
[[Category: Alexander, R S.]]
[[Category: Bai, S.]]
[[Category: Bai, S.]]
[[Category: Clark, C.G.]]
[[Category: Clark, C G.]]
[[Category: Ellis, C.D.]]
[[Category: Ellis, C D.]]
[[Category: Han, Q.]]
[[Category: Han, Q.]]
[[Category: He, M.Y.]]
[[Category: He, M Y.]]
[[Category: Knabb, R.M.]]
[[Category: Knabb, R M.]]
[[Category: Lam, P.Y.S.]]
[[Category: Lam, P Y.S.]]
[[Category: Li, R.]]
[[Category: Li, R.]]
[[Category: Luettgen, J.M.]]
[[Category: Luettgen, J M.]]
[[Category: Pinto, D.J.P.]]
[[Category: Pinto, D J.P.]]
[[Category: Quan, M.L.]]
[[Category: Quan, M L.]]
[[Category: Sun, J.H.]]
[[Category: Sun, J H.]]
[[Category: Teleha, C.A.]]
[[Category: Teleha, C A.]]
[[Category: Wexler, R.R.]]
[[Category: Wexler, R R.]]
[[Category: Wong, P.C.]]
[[Category: Wong, P C.]]
[[Category: IK8]]
[[Category: IK8]]
[[Category: coagulation cascade]]
[[Category: coagulation cascade]]
[[Category: factor xa]]
[[Category: factor xa]]


''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:29:55 2007''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:12:29 2008''

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA