Present Clinical Status of Thrombin Inhibitors

Ofher than argatroban, fhe only non-peptidic fhrombin inhibitors to have reached phase III clinical trials are the simple tripeptide analogue melagatran and its orally available pro-drug ximelagatran from AstraZeneca [5] (Fig. 7.15). For a recent clinical status review, see [80]. 

Thrombin inhibition is a fruitful source of raw data for the study of molecular recognition. Several groups have determined, published, and deposited coordinates for sets of high-resolution X-ray crystal structures. In combination with binding and kinetic data, it is now possible to map the thrombin active site in some detail in terms of both structural changes and the energies of interactions. 

Heuristic models based on the binding of peptidomimetic inhibitors pointed to hydrophobic interactions in the D and P pockets and optimal hydrogen bonding to Gly216 and Aspl89 as being vital for good inhibition. 

More recent experience, coming from a wide variety of sources, shows that for acceptable affinity the hydrophobic interactions have to be maintained and good surface complementarity is essential (no holes), but it is not a requirement that all possible hydrogen bonds are made to Gly216 and Aspl89. 

Given the progress made so far, it is to be hoped that systems such as thrombin will continue to be actively employed to further our understanding of inter-molecular interactions. 

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