3m35: Difference between revisions
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[[Image: | ==Trypsin in complex with the inhibitor 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423)== | ||
<StructureSection load='3m35' size='340' side='right' caption='[[3m35]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3m35]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3M35 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3M35 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=M35:1-[3-(AMINOMETHYL)PHENYL]-N-[3-FLUORO-2-(METHYLSULFONYL)BIPHENYL-4-YL]-3-(TRIFLUOROMETHYL)-1H-PYRAZOLE-5-CARBOXAMIDE'>M35</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3m37|3m37]], [[3m36|3m36]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3m35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3m35 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3m35 RCSB], [http://www.ebi.ac.uk/pdbsum/3m35 PDBsum]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/m3/3m35_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor. | |||
Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyam ide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1).,Pruitt JR, Pinto DJ, Galemmo RA Jr, Alexander RS, Rossi KA, Wells BL, Drummond S, Bostrom LL, Burdick D, Bruckner R, Chen H, Smallwood A, Wong PC, Wright MR, Bai S, Luettgen JM, Knabb RM, Lam PY, Wexler RR J Med Chem. 2003 Dec 4;46(25):5298-315. PMID:14640539<ref>PMID:14640539</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Trypsin|Trypsin]] | *[[Trypsin|Trypsin]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Trypsin]] | [[Category: Trypsin]] | ||
[[Category: Alexander, R S | [[Category: Alexander, R S]] | ||
[[Category: Digestion]] | [[Category: Digestion]] | ||
[[Category: Disulfide bond]] | [[Category: Disulfide bond]] | ||
Revision as of 11:22, 9 December 2014
Trypsin in complex with the inhibitor 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423)Trypsin in complex with the inhibitor 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423)
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFactor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor. Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyam ide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1).,Pruitt JR, Pinto DJ, Galemmo RA Jr, Alexander RS, Rossi KA, Wells BL, Drummond S, Bostrom LL, Burdick D, Bruckner R, Chen H, Smallwood A, Wong PC, Wright MR, Bai S, Luettgen JM, Knabb RM, Lam PY, Wexler RR J Med Chem. 2003 Dec 4;46(25):5298-315. PMID:14640539[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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