2jew
From Proteopedia
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'''CRYSTAL STRUCTURE OF ((2S)-5-AMINO-2-((1-N-PROPYL-1H-IMIDAZOL-4-YL)METHYL)PENTANOIC ACID) UK396,082 A TAFIA INHIBITOR, BOUND TO ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASEB''' | '''CRYSTAL STRUCTURE OF ((2S)-5-AMINO-2-((1-N-PROPYL-1H-IMIDAZOL-4-YL)METHYL)PENTANOIC ACID) UK396,082 A TAFIA INHIBITOR, BOUND TO ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASEB''' | ||
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[[Category: Moore, R S.]] | [[Category: Moore, R S.]] | ||
[[Category: 3d-structure]] | [[Category: 3d-structure]] | ||
| - | [[Category: | + | [[Category: Carboxypeptidase]] |
| - | [[Category: | + | [[Category: Carboxypeptidase b]] |
| - | [[Category: | + | [[Category: Direct metal-binding]] |
| - | [[Category: | + | [[Category: Exopeptidase]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Metalloprotease]] |
| - | [[Category: | + | [[Category: Protease]] |
| - | [[Category: | + | [[Category: Zinc]] |
| - | [[Category: | + | [[Category: Zymogen]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 08:48:16 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 05:48, 4 May 2008
CRYSTAL STRUCTURE OF ((2S)-5-AMINO-2-((1-N-PROPYL-1H-IMIDAZOL-4-YL)METHYL)PENTANOIC ACID) UK396,082 A TAFIA INHIBITOR, BOUND TO ACTIVATED PORCINE PANCREATIC CARBOXYPEPTIDASEB
Overview
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.
About this Structure
2JEW is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.
Reference
Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis., Bunnage ME, Blagg J, Steele J, Owen DR, Allerton C, McElroy AB, Miller D, Ringer T, Butcher K, Beaumont K, Evans K, Gray AJ, Holland SJ, Feeder N, Moore RS, Brown DG, J Med Chem. 2007 Nov 29;50(24):6095-103. Epub 2007 Nov 9. PMID:17990866 Page seeded by OCA on Sun May 4 08:48:16 2008
