Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

Abstract

The trypsin-like serine protease thrombin is a multifunctional key enzyme at the final step of the coagulation cascade and is involved in the regulation of hemostasis and thrombosis. An increased activation of coagulation can result in severe thromboembolic disorders, one of the major reasons responsible for mortality and morbidity in western world. Therefore, an effective, safe, and orally available thrombin inhibitor could be a useful anticoagulant drug for the daily prophylaxis of venous and arterial thrombosis and prevention of myocardial infarction for high-risk patients. Synthetic thrombin inhibitors have a long history; initial compounds were derived from electrophilic ketone- and aldehyde-analogs of arginine. First potent leads of non-covalent inhibitors were developed in the early eighties, which were further optimised in the nineties, after the X-ray structure of thrombin became available. In the meantime a huge number of highly active and selective inhibitors has been published, however, only a few of them have an appropriate pharmacokinetic and pharmacodynamic overall profile, which could justify their further development. Very recently, with Ximelagatran a first orally available thrombin inhibitor has been approved in France for the prevention of venous thromboembolic events in major orthopaedic surgery after successful clinical phase III. However, it still has to be awaited, whether the extensive clinical use of Ximelagatran can demonstrate for the first time that direct thrombin inhibitors offer a real benefit in terms of efficacy and safety over established antithrombotic therapies. This review summarizes the current status of synthetic thrombin inhibitors with a focus on more recently published and promising new compounds.

More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin

“…1 Most of the early development programs followed a strategy to address the S1 specificity pocket of the enzyme with basic molecular moieties to mimic the arginine side chain of the natural substrate fibrinopeptide A. 2 However, as a consequence of being positively charged under physiological conditions, they generally have poor pharmacokinetic properties.…”

Direct thrombin inhibitors – a survey of recent developments

“…Because of its central role in coagulation and hemostasis, thrombin is considered to be an ideal target for anticoagulant therapy, and tremendous efforts have been undertaken particularly during the last two decades to develop preferentially small-molecule direct thrombin inhibitors [reviewed in refs. 19,20].…”

Proteases: Nature’s Destroyers and the Drugs that Stop Them

“…However, there are drawbacks to using warfarin, such as a narrow therapeutic range and many adverse interactions [41]. These factors result in a limited efficacy of warfarin and were the driving force for the development of orally available, small molecule inhibitors of thrombin [37,55] The drugs available in the clinic are described below:…”

“…However, there are drawbacks to using warfarin, such as a narrow therapeutic range and many adverse interactions [41]. These factors result in a limited efficacy of warfarin and were the driving force for the development of orally available, small molecule inhibitors of thrombin [37,55] The drugs available in the clinic are described below:The development of melagatran and ximelagatran are early examples of computer modeling to direct the synthesis of drug leads [34,36,56]. An excellent review describing the 20-year development of these drugs has been published [56].…”