Amidoximes and their masked derivatives as prodrugs of amidines – arginine mimetics

O. V. Ovdiichuk, O. V. Hordiyenko

Abstract


The literature data concerning the use of amidoximes as prodrugs of amidines – arginine mimics – have been systematized. The advantages of the use of amidoximes as prodrugs that have become a tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents has been highlighted. The mechanism of their in vivo activation by the mARC-containing N-reductive enzyme system to release the active parent drug of amidoximes has been described. The data on application of the “amidoximes instead of amidines” strategy in the prodrug design have been summarized. The examples of prodrugs with a wide range of biological activities such as antiprotozoal and antithrombotic activity, as well as inhibitors of serine proteases of the sulfonamide type, antiviral prodrugs have been given. They are either introduced into production or are at the stage of clinical trials. In addition, the synthetic methods for amidoximes, and the synthesis of the known prodrugs have been also shown. The new approach to the drug modifi cation – the use of double prodrugs has been described. This strategy allows to obtain the derivatives with less basicity and improved lipophilicity,therefore, with better bioavailability. The synthesis of a single commercial oral thrombin inhibitor dabigatran etexilate (Pradaxa) as a dabigatran double prodrug, as well as amidine and amidoxime derivatives of the antiviral oseltamivir (Tamifl u) has been presented. 1,2,4-Oxadiazoles, masked amidoxime prodrugs have been used in the design of potential antimalarial, antifungal drugs and in order to obtain new oral GPIIb/IIIa antagonists.

Keywords


amidoximes; prodrugs; synthesis; amidines; double prodrugs; bioactivation; bioavailability

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