Prodrugs chemical hydrolysis

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

This section discusses prodrugs whose hydrolysis (be it chemical and/or enzymatic) is followed by breakdown of the pro-moiety with liberation of a carbonyl compound. In the glycolic acid (= hydroxyacetic acid) esters briefly examined in Sect. 8.3.1, the pro-moiety once cleaved breaks down enzymatically. In the rest of the section, however, the cleaved pro-moiety will be seen to break down spontaneously. 

R = Me, Et, and PhCH2, respectively Fig. 8.1). In 80% human plasma at pH 7.4 and 37°, these model prodrugs were hydrolyzed with tm values of 3.5, 16, and 2.6 min, respectively [59]. Such rates of enzymatic hydrolysis are comparable to those of various carbamoylmethyl esters of benzoic acid (Table 8.2). It is important to note that the direct liberation of benzoic acid by Reaction a (Fig. 8.1) was severalfold faster than the competitive Reaction b. Reaction c was very slow in human plasma (tm > 100 h). In HO -catalyzed hydrolysis, the opposite regioselectivity was seen, with the terminal ester bridge being cleaved markedly faster than the central one. No data appears to be available on chemical hydrolysis at neutral pH. 

To conclude this section, we compare large series of potential prodrugs of /1-blockers, comprising esters of linear, branched, and cyclic alkanoic acids, as well as benzoic acid esters to be discussed in Sect. 8.5.6. In the case of esters of timolol (8.85, R = H), the tm values of chemical hydrolysis at... 

Similarly, chemical hydrolysis of a number of a-amino acyl prodrugs of metronidazole (8.100, R=H see Sect. 8.5.4) was compared to the serum-catalyzed reaction [135][136]. The amino acids used for esterification included alanine, glycine, isoleucine, leucine, lysine, phenylalanine, and valine. Under physiological conditions of pH and temperature, ty2 values for hydrolysis in human serum ranged from 4.5 min for the Phe ester to 96 h for the lie ester. A good linear relationship was established between the log of the rate constant of enzymatic hydrolysis and the log of the rate constant of HO-cata-... 

Thus, there will be a major difference in the design of carbamate prodrugs of phenols and alcohols, as illustrated below. In the case of alcohols, both W-monosubstituted and AOV-disubstituted carbamates will a priori be stable. For phenols, AUV-disubslilulcd carbamates are also stable toward chemical hydrolysis, whereas the /V-monosubsti luted carbamates are, as a rule, more labile toward chemical hydrolysis. However, some notable exceptions are discussed below. In addition, many other factors beside chem-... 

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. 

G. N. Wernly-Chung, J. M. Mayer, A. Tsantih-Kakouhdou, B. Testa, Structure-Reactivity Relationships in the Chemical Hydrolysis of Prodrug Esters of Nicotinic Acid , Int. J. Pharm. 1990, 63, 129-134. 

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

Intramolecular cyclizations are not restricted to attack by a nucleophilic nitrogen (basic amino or acidic amido group). They can also be catalyzed by a nucleophilic oxygen as found in a carboxylate, phenolic, or alcoholic group. Illustration of the catalytic role of a carboxylate group can be found in hemiester prodrugs of phenol (taken as model compound) or paracetamol (Fig. 6 R = H or NHCOCH3, respectively). In addition to enzymatic hydrolysis, three mechanisms of chemical hydrolysis were seen, namely, acid-catalyzed, base-catalyzed, and an intramolecular nucleophilic attack. 

Capecitabine is an example of a prodrug chemical delivery system that requires a series of enzymatic steps for conversion to the active antitumor drug species. S-fluorouracil (Scheme 5-24). Tumors located in tissues with high levels of the required enzymes. should respond best to treaunent with capecitabine. Esterase activity occurs primarily in the liver, allowing the intact e.ster capecitabine to be the absorbed species following oral administration. The ester hydrolysis product itself shows some specific toxicity towani... 

Oximes of enones (98, 100, and 101) have been used as prodrugs of contraceptive norethindrone (97) and levonorgestrel (99). The oximes are highly bioavailable and are converted in vivo through chemical hydrolysis to their corresponding active drugs.56 57... 

Mannich base prodrugs are regenerated by chemical hydrolysis (Section 2.8) without enzymatic catalysis (30). Various other chemical approaches can be used to achieve increased skin permeability by enhancing both water solubility and lipid solubility (31). 

Mixed anhydrides represent original attempts for preparing prodrugs of carboxylic or phosphonic acid. Clodronic acid dianhydrides (Fig. 33.7), for example, were shown to be novel bioreversible prodrugs of clodronate. They are more lipophilic than the parent clodronate, stable against chemical hydrolysis, and hydrolyse enzymatically to clodronate in human serum. ... 

As already mentioned, isoxazoles such as I FT are prodrugs and are not sufficiently persistent in plants to inhibit the HP PD enzyme. It is the first metabolite of isoxaflutole, the so-called DKN (diketonitrile) 3-cyclopropyl-2-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-oxopropanenitrile (25) that is the herbicidally active entity. In soil, and also in plants, I FT undergoes rapid conversion into DKN [25]. In aqueous solutions there is an influence of temperature and pH on the chemical hydrolysis of IFT to DKN. The hydrolysis increases with increasing pH and temperature for 295 K and pH 9.3 the rate of degradation was 100-fold faster than at pH 3.8. (Scheme 4.4.7) [26]. The DT50 in water is 11 days at pH 5, 20 h at pH 7 and 3 h at pH 9 [22]. 

---