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Bioorg Med Chem. 2011 Mar 15;19(6):1907-14. doi: 10.1016/j.bmc.2011.01.066. Epub 2011 Feb 3.

Synthesis and biological evaluation of L-valine-amidoximeesters as double prodrugs of amidines.

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Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstr. 76-78, D-24118 Kiel, Germany.


In general, drugs containing amidines suffer from poor oral bioavailability and are often converted into amidoxime prodrugs to overcome low uptake from the gastrointestinal tract. The esterification of amidoximes with amino acids represents a newly developed double prodrug principle creating derivatives of amidines with both improved oral availability and water solubility. N-valoxybenzamidine (1) is a model compound for this principle, which has been transferred to the antiprotozoic drug pentamidine (8). Prodrug activation depends on esterases and mARC and is thus independent from activation by P450 enzymes. Therefore, drug-drug interactions or side effects will be minimized. The synthesis of these two compounds was established, and their biotransformation was studied in vitro and in vivo. Bioactivation of N-valoxybenzamidine (1) and N,N'-bis(valoxy)pentamidine (7) via hydrolysis and reduction has been demonstrated in vitro with porcine and human subcellular enzyme preparations and the mitochondrial Amidoxime Reducing Component (mARC). Moreover, activation of N-valoxybenzamidine (1) by porcine hepatocytes was studied. In vivo, the bioavailability in rats after oral application of N-valoxybenzamidine (1) was about 88%. Similarly, N,N'-bis(valoxy)pentamidine (7) showed oral bioavailability. Analysis of tissue samples revealed high concentrations of pentamidine (8) in liver and kidney.

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