Drug degradation rates depend on the chemical structure of the drug, as described earlier. Most often, structure modifications are performed to enhance activity or to have a positive impact on the in vivo properties of the drug. However, for drugs that are very chemically unstable, development of more stable analogs should be possible through appropriate structure modifications.
An example of analog development to effect stabilization is the masking of reactive hydroxyl groups. Degradation of erythromycin via 6,9-hemiketal breakdown under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl. For example, the acid stability of clarithromycin is 340 times greater than that of erythromycin (Fig. 118).508
The effect of substituents on degradation rate has been reported for hydrolysis of water-soluble prodrugs of phenytoin,509 and (aminomethyl)benzoate ester prodrugs of
acyclovir.510 As shown in Fig. 119, the acid-catalyzed degradation rate of enaminones, formed between a primary amine and a 1,3-dicarbonyl compound, decreased as the pKa of the 1,3-dicarbonyl compound decreased, because the rate-determining step in the degradation was proton addition to the vinyl carbon of the enaminone.511
Although many studies have been reported on the stabilization of drugs against enzymatic degradation in vivo, such as the protection of peptides from metabolism by modifying the N-terminal with an ethyl group,512 this topic will not be covered here.
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