2JEW

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

2JEW の概要

• エントリーDOI: 10.2210/pdb2jew/pdb
• 関連するPDBエントリー: 1NSA 1PBA 1Z5R 1ZG7 1ZG8 1ZG9
• 分子名称: CARBOXYPEPTIDASE B, ZINC ION, (2S)-5-AMINO-2-[(1-PROPYL-1H-IMIDAZOL-4-YL)METHYL]PENTANOIC ACID, ... (4 entities in total)
• 機能のキーワード: carboxypeptidase, carboxypeptidase b, direct metal-binding, metalloprotease, protease, hydrolase, zinc, zymogen, exopeptidase
• 由来する生物種: SUS SCROFA (PIG)
• 細胞内の位置: Secreted : P09955
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35109.99

構造登録者

Brown, D.G.,Moore, R.S. (登録日: 2007-01-24, 公開日: 2007-11-20, 最終更新日: 2024-11-20)

主引用文献

Bunnage, M.E.,Blagg, J.,Steele, J.,Owen, D.R.,Allerton, C.,McElroy, A.B.,Miller, D.,Ringer, T.,Butcher, K.,Beaumont, K.,Evans, K.,Gray, A.J.,Holland, S.J.,Feeder, N.,Moore, R.S.,Brown, D.G.
Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.
J. Med. Chem., 50:6095-6103, 2007

PubMed Abstract: 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.

PubMed: 17990866
DOI: 10.1021/jm0702433

実験手法

X-RAY DIFFRACTION (1.4 Å)