Case Study: Ximelagatran: A Double Prodrug of Melagatran
Ximelagatran was designed to increase the bioavailability of melagatran, a potent thrombin inhibitor, by eliminating charges and thus increasing the lipophilicity of the molecule. Melagatran, like most other thrombin inhibitors, contains a strongly basic benzamidine group with a pKa of 11.5 that is protonated at the pH of the intestinal tract and hinders intestinal absorption. Furthermore, melagatran also contains an acidic carboxylic group with a pKa of 2.0, which is ionized at physiological pH. Melagatran also contains a secondary amine with a pKa of 7.0. The effect of the charges on the oral absorption of melagatran was observed when the compound was initially dosed orally and a low and variable bioavailability of 3–7% was observed (Gustafsson et al., 2001).
KeywordsNitric Oxide Ethyl Ester Secondary Amine Oral Absorption Direct Thrombin Inhibitor
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