Metabolic Stabilization and Modulation of Reaction Centers

A factor limiting the clinical usefulness of many pharmaceuticals is their too rapid metabolic degradation. In the best case this leads to low effectiveness and puts a heavy load on the liver and kidneys. In other cases the drug seems to fulfill is purpose effectively but it cannot be used clinically because of the formation of toxic or mutagenic metabolites [7]. 

The key to many of these degradation processes is oxidative metabolism by the cytochrome P450 enzyme family [10]. Cytochrome P450 oxidation is most easy for electron-rich -electron systems, for example aromatic moieties or olefinic substructures, from which epoxides are generated. These epoxides are often potent electrophiles, intercalating into DNA and reacting with all kinds of nucleophile, for example nucleobases, amines, or thiols. Metabolic processes like this are the reason for the mutagenicity of many polycyclic arenes. 

Other types of P450-mediated metabolic processes are the oxidative hydroxy-lation of aliphatic compounds with labile hydrogen substituents and oxidative demethylations of aromatic methoxy groups or methylamines. 

Among other modifications, selective fluorination starting from the first lead structure (top) results in compounds with dramatically improved effectiveness [53b, c]. 

Many other metabolic degradation pathways are either initiated by reactions involving generation of transient carbocations or pass through a transition state with highly positive charge density on a carbon center. Reactions in this category are the acidic hydrolysis of acetals, aminals, or enol ethers, and the oxidation of alcohols to ketones via a hydride-transfer mechanism. 

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