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The Peptidylglycine α‐Amidating Monooxygenase (PAM): A Novel Prodrug Strategy For Amidoximes And N‐Hydroxyguanidines?

D. Schade, Joscha Kotthaus, Helen Hungeling, J. Kotthaus, B. Clement
Published 2009 · Chemistry, Medicine

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In recent decades the concept of targeted prodrug design has attracted much interest in the field of pharmaceutical and medicinal chemistry. The use of prodrugs allows unfavorable physicochemical, pharmacokinetic and/or pharmacodynamic properties of drug candidates to be overcome. Amidine and guanidine moieties are valuable pharmacophoric groups since they can mimic arginine residues in biological structures. They often contribute to high affinities of small molecules to their target proteins by strong ionic and Hbond interactions. In many cases, their replacement with other functionalities leads to concomitant significant loss of affinity. However, under physiological conditions these strongly basic structures exist in their cationic form and are therefore usually unable to pass through mucosal membranes. Without specific transporter mechanisms, amidines and guanidines are poorly absorbed in the gastrointestinal tract after oral application. In order to mask their basic properties and thereby improve passive diffusion, several prodrug strategies have been pursued in the past few years. To date, most of these prodrug principles were applied particularly to the amidine moiety of drugs belonging to a wellstudied class of antithrombotics. Among these principles, the amidoxime function has been a promising concept since the N-hydroxylation leads to a significant decrease in basicity and an increase in lipophilicity. Furthermore, the extensive in vivo reduction of such amidoximes, that is the required bioactivation, has been demonstrated for benzamidoxime as a model compound, the antiprotozoic prodrug pentamidine diamidoxime, the GPIIb/IIIa antagonist sibrafiban, the thrombin inhibitor ximelagatran, and several more N-hydroxylated prodrugs. 5] Notably, this bioactivation proceeds in a CYP450-independent manner; we recently identified a molybdenum-containing enzyme (mARC) that is largely responsible for this N-reduction. In contrast to amidoximes, N-hydroxyguanidines have not yet found application as prodrugs for guanidines. Their efficient N-reduction, however, has already been demonstrated for guanoxabenz and N-hydroxydebrisoquine. In this context, a major issue in the applicability of N-hydroxyguanidines as guanidine prodrugs may be their chemical instability in terms of hydrolysis and oxidation, requiring further stabilizing modifications. Previous prodrug strategies for amidoximes (and N-hydroxyguanidines) are now targeted to optimize metabolic and physicochemical stability, thereby further enhancing oral bioavailACHTUNGTRENNUNGability and their general applicability. By additional Oand/or N-substitution, presystemic reduction is expected to be prevented, which otherwise leads to decreased oral absorption. Furthermore, tendencies for chemical degradations, particularly regarding N-hydroxyguanidines, may be circumvented. Moreover, a specific prodrug group may allow for cellor tissuetargeting, thereby minimizing side effects and maximizing the ACHTUNGTRENNUNGdesired therapeutic effects. An example of an O-alkylated prodrug (such as 4, Figure 1) is the O-methylamidoxime DB844, an antiparasitic agent with good oral bioavailability and in vivo efficacy. The required
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