Prodrugs metabolic considerations

Balant, L.P. Doelker, E. Metabolic considerations in prodrug design. In Burger s Medicinal Chemistry and Drug Discovery, 5thEd. Wolff, M.E., Ed. Wiley New York, 1995 1,949-982. 

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. 

Sometimes, ADME considerations can be used to the advantage of the drug designer. This is particularly true when applied to the concept of a prodrug. A prodrag is a drug molecule that is biologically inactive until it is activated by a metabolic process. The active compound is released as a metabolite. 

The pseudodipeptide amides represented a major advance in the substrate-based design of FTIs. They removed the metabolic liability of the prodrug, were cell active, and were considerably simpler chemically. However, the majority of pseudodipeptide amides were not potent enough and too cytotoxic to demonstrate activity in cell culture. Although the potency issue was perceived as solvable, the dark cloud of nonspecific cytotoxicity hovered over this particular class of compounds like an unwelcome visitor. Changes to the molecule which virtually destroyed FTase activity had no effect on the level of cytotoxicity, indicating that the observed toxicity was unlikely to be mechanism related. 

Dopamine receptor agonists used in the therapy against Parkinson s disease often possess phenolic or catecholic moieties, which lead to low oral bioavailabilities for these compounds since they undergo considerable metabolic degradation in the liver.161 Because of the low oral bioavailability of hydroxylated compounds, there has been a lot of interest in the development of prodrugs of such compounds, thereby circumventing the metabolic degradation. 

The difference between pyrazoxyfen and pyrazolynate is only the chosen prodrug system. In plants, both herbicides were metabolized to 4-(2,4-dichlorobenzoyl)-l,3-dimethyl-5-hydroxypyrazole (8). Pyrazolynate is only slightly soluble in water, but, once dissolved, is rapidly hydrolyzed to the herbicidally active metabolite [11]. In contrast, pyrazoxyfen shows considerable stability in aqueous solutions [16]. 

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