2fzz
From Proteopedia
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| - | [[Image:2fzz.gif|left|200px]] | + | [[Image:2fzz.gif|left|200px]] |
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| - | '''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''' | + | {{Structure |
| + | |PDB= 2fzz |SIZE=350|CAPTION= <scene name='initialview01'>2fzz</scene>, resolution 2.20Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=5QC:1-(3-AMINO-1,2-BENZISOXAZOL-5-YL)-6-(2'-{[(3R)-3-HYDROXYPYRROLIDIN-1-YL]METHYL}BIPHENYL-4-YL)-3-(TRIFLUOROMETHYL)-1,4,5,6-TETRAHYDRO-7H-PYRAZOLO[3,4-C]PYRIDIN-7-ONE'>5QC</scene> | ||
| + | |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] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''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''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2FZZ is a [ | + | 2FZZ 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=2FZZ OCA]. |
==Reference== | ==Reference== | ||
| - | 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 (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa., Pinto DJ, Orwat MJ, Quan ML, Han Q, Galemmo RA Jr, Amparo E, Wells B, Ellis C, He MY, Alexander RS, Rossi KA, Smallwood A, Wong PC, Luettgen JM, Rendina AR, Knabb RM, Mersinger L, Kettner C, Bai S, He K, Wexler RR, Lam PY, Bioorg Med Chem Lett. 2006 Aug 1;16(15):4141-7. Epub 2006 May 30. PMID:[http:// | + | 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 (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa., Pinto DJ, Orwat MJ, Quan ML, Han Q, Galemmo RA Jr, Amparo E, Wells B, Ellis C, He MY, Alexander RS, Rossi KA, Smallwood A, Wong PC, Luettgen JM, Rendina AR, Knabb RM, Mersinger L, Kettner C, Bai S, He K, Wexler RR, Lam PY, Bioorg Med Chem Lett. 2006 Aug 1;16(15):4141-7. Epub 2006 May 30. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16730984 16730984] |
[[Category: Coagulation factor Xa]] | [[Category: Coagulation factor Xa]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:58:46 2008'' |
Revision as of 14:58, 20 March 2008
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| , resolution 2.20Å | |||||||
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| Ligands: | |||||||
| Activity: | Coagulation factor Xa, with EC number 3.4.21.6 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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
Contents |
Overview
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
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
2FZZ is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa., Pinto DJ, Orwat MJ, Quan ML, Han Q, Galemmo RA Jr, Amparo E, Wells B, Ellis C, He MY, Alexander RS, Rossi KA, Smallwood A, Wong PC, Luettgen JM, Rendina AR, Knabb RM, Mersinger L, Kettner C, Bai S, He K, Wexler RR, Lam PY, Bioorg Med Chem Lett. 2006 Aug 1;16(15):4141-7. Epub 2006 May 30. PMID:16730984
Page seeded by OCA on Thu Mar 20 16:58:46 2008
