Direct thrombin inhibitor

Types

There are three types of DTIs, dependent on their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site. The third class of inhibitors, which are gaining importance recently, is the allosteric inhibitors.

Bivalent

Hirudin and derivatives were originally discovered in Hirudo medicinalis:

• Hirudin
• Bivalirudin (transient inhibition - is cleaved by thrombin)
• Lepirudin
• Desirudin

Univalent

Univalent DTIs include:

• Argatroban
• Inogatran
• Melagatran (and its prodrug ximelagatran)
• Dabigatran

Allosteric inhibitors

Thrombin demonstrates a high level of allosteric regulation. Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant. Some of the allosteric inhibitors discovered include DNA aptamers, benzofuran dimers, benzofuran trimers, as well as polymeric lignins. A new sulfated β-O4 lignin (SbO4L) has been discovered which has shown a dual mechanism of action for anti-thrombosis. This SbO4L shows allosteric inhibition of thrombin for fibrinogen, while providing a competitive inhibition of thrombin interaction with platelet glycoprotein Ibα (GPIbα), thereby preventing thrombin mediated platelet aggregation. However, despite the growing interest and the advances in allosterism, no allosteric thrombin inhibitor has yet reached the stage of clinical trials.