2fzz: Difference between revisions
New page: left|200px<br /> <applet load="2fzz" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fzz, resolution 2.20Å" /> '''Factor Xa in comple... |
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[[Image:2fzz.gif|left|200px]]<br /> | [[Image:2fzz.gif|left|200px]]<br /><applet load="2fzz" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2fzz" size=" | |||
caption="2fzz, resolution 2.20Å" /> | caption="2fzz, resolution 2.20Å" /> | ||
'''Factor Xa in complex with the inhibitor 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl)methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one'''<br /> | '''Factor Xa in complex with the inhibitor 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl)methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one'''<br /> | ||
==Overview== | ==Overview== | ||
Attempts to further optimize the pyrazole factor Xa inhibitors centered on | Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyr rolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-py ridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2FZZ 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 5QC 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:// | 2FZZ 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=5QC:'>5QC</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=2FZZ 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: 5QC]] | [[Category: 5QC]] | ||
[[Category: blood coagulation factor]] | [[Category: blood coagulation factor]] | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:26:49 2008'' | ||
