2jew

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spinqualitylabelsall models 2jew, resolution 1.4Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 with and as ligands. Active as Carboxypeptidase B, with EC number 3.4.17.2 Known structural/functional Sites: , and . 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 9;. PMID:17990866

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