Prolinamide derivatives as thrombin inhibitors for the treatment of thrombin-mediated diseases: a patent evaluation of US2013296245.

BACKGROUND

Thrombotic disorders can lead to deep vein thrombosis, myocardial infarction and stroke. Thrombin plays a vital role in cascade reaction of blood coagulation, inhibition of the activity of thrombin can block the formation of thrombus and direct thrombin inhibitor has a prospect to overcome the limitations in application of the traditional anticoagulant drugs.

METHODS

The current patent US2013296245 describes a series of prolinamide derivatives with formula (I) as thrombin inhibitors. These new compounds are defined to be pharmaceutically acceptable salts derived from pharmaceutically acceptable inorganic acid and organic acid, and pharmaceutically acceptable prodrug where N-alkoxycarbonyl is protected or carboxylic acid is protected by ester.

CONCLUSIONS

The patent used formamidine and its N-alkoxycarbonyl-protected derivatives as the P1 group; these groups were less basic compared with the traditional guanidine group, so their lipophilicity could be optimized to achieve oral absorption. Furthermore, these pharmaceutically acceptable prodrugs where N-alkoxycarbonyl is protected or carboxylic acid is protected by ester could achieve prolonged half-life for a convenient once- or twice-daily oral dosing. These efforts gave a new hope and confidence to treat thrombotic disorders with selective and orally active thrombin inhibitors.