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

摘要

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.