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The discovery of dabigatran etexilate.

van Ryn J, Goss A, Hauel N, Wienen W, Priepke H, Nar H, Clemens A - Front Pharmacol (2013)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of CardioMetabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss, Baden-Württemberg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

(A) Surface representation of FIIa bound to dabigatran. The insert shows a zoom into the active site cleft of the enzyme. The most prominent feature of the ligand-protein interaction interface is the deep S1 pocket in which the benzamidine moiety binds. The 60-loop insertion of FIIa with the prominent Trp-60D occludes a hydrophobic S2 pocket in which the methylbenzimidazole of dabigatran nicely fits. The S4 pocket is rather shallow pocket that prefers to bind aromatic moieties of inhibitors. Dabigatran occupies the S4 pocket with its pyridyl ring that forms an edge-on CH…π interaction with Trp-215 at the floor of the pocket and places its propionic acid group into the solvent exposed S3 pocket. (B) Effect of increasing concentrations of dabigatran on diluted thrombin time measurements in different species. The EC(T2) and EC(T3) represent the effective concentration of dabigatran to prolong the clotting time either twofold or threefold. Data represented as mean ± SE, n = 4–5.
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Figure 2: (A) Surface representation of FIIa bound to dabigatran. The insert shows a zoom into the active site cleft of the enzyme. The most prominent feature of the ligand-protein interaction interface is the deep S1 pocket in which the benzamidine moiety binds. The 60-loop insertion of FIIa with the prominent Trp-60D occludes a hydrophobic S2 pocket in which the methylbenzimidazole of dabigatran nicely fits. The S4 pocket is rather shallow pocket that prefers to bind aromatic moieties of inhibitors. Dabigatran occupies the S4 pocket with its pyridyl ring that forms an edge-on CH…π interaction with Trp-215 at the floor of the pocket and places its propionic acid group into the solvent exposed S3 pocket. (B) Effect of increasing concentrations of dabigatran on diluted thrombin time measurements in different species. The EC(T2) and EC(T3) represent the effective concentration of dabigatran to prolong the clotting time either twofold or threefold. Data represented as mean ± SE, n = 4–5.

Mentions: 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). However it was not orally active due to its polarity and the compound was converted into an orally active prodrug (dabigatran etexilate; Himmelsbach et al., 1995). Given orally to rhesus monkeys, this prodrug exhibited strong and long lasting anticoagulant effects as measured by the activated partial thromboplastin time (aPTT) ex vivo (Wienen et al., 2007a). Based on its promising profile, dabigatran etexilate was selected for clinical development.


The discovery of dabigatran etexilate.

van Ryn J, Goss A, Hauel N, Wienen W, Priepke H, Nar H, Clemens A - Front Pharmacol (2013)

(A) Surface representation of FIIa bound to dabigatran. The insert shows a zoom into the active site cleft of the enzyme. The most prominent feature of the ligand-protein interaction interface is the deep S1 pocket in which the benzamidine moiety binds. The 60-loop insertion of FIIa with the prominent Trp-60D occludes a hydrophobic S2 pocket in which the methylbenzimidazole of dabigatran nicely fits. The S4 pocket is rather shallow pocket that prefers to bind aromatic moieties of inhibitors. Dabigatran occupies the S4 pocket with its pyridyl ring that forms an edge-on CH…π interaction with Trp-215 at the floor of the pocket and places its propionic acid group into the solvent exposed S3 pocket. (B) Effect of increasing concentrations of dabigatran on diluted thrombin time measurements in different species. The EC(T2) and EC(T3) represent the effective concentration of dabigatran to prolong the clotting time either twofold or threefold. Data represented as mean ± SE, n = 4–5.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569592&req=5

Figure 2: (A) Surface representation of FIIa bound to dabigatran. The insert shows a zoom into the active site cleft of the enzyme. The most prominent feature of the ligand-protein interaction interface is the deep S1 pocket in which the benzamidine moiety binds. The 60-loop insertion of FIIa with the prominent Trp-60D occludes a hydrophobic S2 pocket in which the methylbenzimidazole of dabigatran nicely fits. The S4 pocket is rather shallow pocket that prefers to bind aromatic moieties of inhibitors. Dabigatran occupies the S4 pocket with its pyridyl ring that forms an edge-on CH…π interaction with Trp-215 at the floor of the pocket and places its propionic acid group into the solvent exposed S3 pocket. (B) Effect of increasing concentrations of dabigatran on diluted thrombin time measurements in different species. The EC(T2) and EC(T3) represent the effective concentration of dabigatran to prolong the clotting time either twofold or threefold. Data represented as mean ± SE, n = 4–5.
Mentions: 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). However it was not orally active due to its polarity and the compound was converted into an orally active prodrug (dabigatran etexilate; Himmelsbach et al., 1995). Given orally to rhesus monkeys, this prodrug exhibited strong and long lasting anticoagulant effects as measured by the activated partial thromboplastin time (aPTT) ex vivo (Wienen et al., 2007a). Based on its promising profile, dabigatran etexilate was selected for clinical development.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of CardioMetabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss, Baden-Württemberg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus