Discovery of Potent & Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor for the Treatment of Thrombosis

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• 作者：Mark E. Bunnage ; Julian Blagg ; John Steele ; Dafydd R. Owen ; Charlotte Allerton ; Andrew B. McElroy ; Duncan Miller ; Tracy Ringer ; Ken Butcher ; Kevin Beaumont ; Karen Evans ; Andrew J. Gray ; Stephen J. Hol
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6095 - 6103
• 全文大小：222K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation andfibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel seriesof imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa)and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggestthat the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has beensupported 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) asa candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model ofvenous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellentpreclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance,and a low volume of distribution, fully consistent with its physicochemical properties of low molecularweight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) haspotential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases inhumans.