THROMBIN INHIBITOR DESIGN

Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fu eled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokin etics and a duration of action sufficient for once or twice a day dosi ng, in order to develop an orally active compound which meets these cr iteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have b een identified by modifying the PI group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resul ted in the development of potent and selective non-covalent inhibitors , thus bypassing the liabilities of the serine trap. Thirdly, oral bio availability has been achieved while maintaining selectivity and effic acy through the incorporation of progressively less basic P1 groups. T he duration of action of these compounds remains to be optimized. Othe r advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.