The discovery of dabigatran etexilate.

Joanne Van Ryn,Herbert Nar,Norbert Hauel,Henning Priepke,Ashley Goss,Andreas Clemens,Wolfgang Wienen

doi:10.3389/fphar.2013.00012

Abstract

Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation. Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and food- and drug–drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

Highlights

Thrombin is a serine protease and is the main effector protease in the blood coagulation cascade (Figure 1A), exhibiting both pro- and anticoagulant properties (Griffin, 1995; Di Cera, 2008)
Dabigatran’s effects in the setting of mechanical valve replacement was investigated in the dose-finding RE-ALIGN phase II study (Van de Werf et al, 2012), the study was discontinued because interim analysis showed an increased incidence of thromboembolic events compared to warfarin
SUMMARY Based on a NAPAP-thrombin X-ray crystal structure a new class of thrombin inhibitors was designed, with the potency of these compounds optimized over several iterative steps

Summary

Introduction

Thrombin is a serine protease and is the main effector protease in the blood coagulation cascade (Figure 1A), exhibiting both pro- and anticoagulant properties (Griffin, 1995; Di Cera, 2008). A lead compound (dabigatran; Figure 2A) was identified because of its favorable selectivity profile and strong in vitro and in vivo activity, exhibiting long anticoagulation duration in rats after i.v. administration and toleration at high doses (Wienen et al, 2007a). EX VIVO ANTIHEMOSTATIC EFFECTS OF DABIGATRAN Significant dose- and time-dependent anticoagulant efficacy ex vivo has been demonstrated after i.v. administration of dabigatran to rats and rhesus monkeys.

Results

Conclusion