Double prodrug

Sarpicillin (10) is a double prodrug of ampicillin in that not only is the carboxy group masked as an ester, but a... 

Cyclization-Activated Double Prodrugs of Amines and Peptides... 

The oxidation of dihydropyridine-based chemical delivery systems (CDSs) pioneered by Bodor and co-workers [176] has been discussed in a previous book (Chapt. 13 in [81]). There, we examined the principles by which such compounds function to deliver drugs to the brain. Here, we focus our attention to the last step in the activation of these double prodrugs, namely hydrolysis to release the drug. 

The derivatization of a basic function is exemplified by the amidine peptidomimetic of structure 8.156 (R = Rr = H), an inhibitor of the platelet membrane glycoprotein GPIIbIIIa [202], The compound is a zwitterion at physiological pH and showed limited oral bioavailability. A double prodrug... 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

Fig. 8.24. Schematic representation of cyclic, double prodrugs of peptides and their mechanism of activation by enzymatic ester cleavage, followed by cyclization-elimination [168][169][238]...

Coumarinic acid is another phenylpropanoic acid pro-moiety used to prepare double prodrugs of amines (in analogy with the phenylpropanamides shown in Fig. 8.23), as well as cyclic prodrugs of a number of peptides (8.189) [242-246], These studies confirm the considerable potential of the cyclic prodrug strategy, such compounds being characterized by metabolic stability to peptidases and good cellular permeation. 

AstraZeneca also entered a molecule (AZD-3409) (Fig. 4) into phase I/II studies [180]. AZD-3409 is a double prodrug inhibiting both FTase and GGTase I. AZD-3409 is converted in vivo into a prodrug, the main component in plasma of dosed animals, which is further metabolized in cells to the active drug. Recently published phase I data indicate that AZD-3409 was well... 

Jarvinen, T., Suhonen, P, Auriola, S., Vepsalainen, J., Peura, P, et al. (1991), 0,0 -( 1,4-Xylylene)bispilocarpic acid esters as new potential double prodrugs of pilocarpine for improved ocular delivery. Part 1. Synthesis and analysis, Int. I. Pharm., 75(2-3), 249-258. 

A number of examples are known for the release of an active drug facilitated by a linear autodegradation process. This can be achieved through chemically unstable intermediates such as a-hydroxy amines, amides, and esters. Many of the double prodrugs discussed earlier belong to this category. 

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

Although amino acid 1 is a potent inhibitor of CMP-KDO synthase (Figure 36.21), a key enzyme in the biosynthesis of the lipopolysaccharide of Gram-negative bacteria, it is unable to reach its cytoplasmic target and is therefore inactive as an antibacterial agent. Simple lipophilic esters are not useful to enhance the delivery of amino acid 1 since they are not cleaved by the bacteria. On the other hand, double prodrug 3 has been found to solve the problem. ... 

Karl-Thomae [82] have also used a double prodrug strategy on BIBU 52 (28) by masking the amidine as a methylcarbamate. Carbamates of amidines are more labile to hydrolysis than normal amine derived carbamates owing to the presence of the electron-withdrawing imino group. The parent BIBU 52 (28) showed no oral activity in the rhesus monkey, whereas the cor-... 

Prodrugs have been designed to improve corneal absorption. This approach has been applied with epinephrine (226-230), terbutaline (231), various prostaglandins (232), phenylephrine (233-235), and pilocarpine (236-241). For some pilocarpine derivatives the double prodrug approach has been used to overcome eye irritation and improve on poor water solubility (240,241) (Section 5.4). 

Stability in aqueous solutions. This stability problem was solved by forming double prodrug pilocarpic acid esters. Because of their blocked hydroxyl group, these compounds are unable to undergo cyclizationto pilocarpine in the absence of hydro lytic enzymes. 

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