Aldehydes and Ketones.Many metabolic routes are possible, including both oxidation
and reduction. However, oxidations are more common. Aldehydes are very susceptible
to oxidation, which is catalyzed by various enzymes including aldehyde oxidase and
aldehyde dehydrogenase; this oxidation yields a carboxylic acid. Ketones, on the other
hand, tend to be stable to oxidation. Conversely, aldehydes are seldom metabolized by
reduction. Ketones, however, frequently undergo reduction to a secondary alcohol; this
is particularly true for α,β-unsaturated ketones.
Carboxylic Acids.Metabolism of carboxylic acids is relatively straightforward. First
and foremost, carboxylic acids undergo a diverse variety of conjugations. Carboxylic
acids conjugate with glucuronic acid, glutamine, and glycine; the resulting conjugates are
water soluble and more easily excreted. Alternatively, carboxylic acids may be oxidized,
especially beta to the carboxyl group.
Esters.Not surprisingly, esters are not metabolically stable. They are readily con-
verted to the corresponding free acid and alcohol via hydrolysis, a process that may be
either base- or acid-catalyzed. Esters are rapidly hydrolyzed throughout many locations
within the body. Orally administered ester-based drugs are quickly hydrolyzed within
the stomach.
Amides.Although similar to esters in terms of being a functional derivative of a car-
boxylic acid, amides, unlike esters, are relatively metabolically stable. In general,
amides are stable to acid- and base-catalyzed hydrolysis. This stability is related to
the overlapping electron clouds within the amide functionality and the corresponding
multiple resonance forms. Amidases are enzymes that can catalyze the hydrolysis of
amides. Nevertheless, amides are much more stable than esters.
Carbonates, Carbamates.The ester portion of both carbonates and carbamates is
hydrolyzed to give the monosubstituted carbonic acid, which is unstable and decomposes
with loss of carbon dioxide. Thus, carbonates are hydrolyzed to give alcohol and carbon
dioxide; carbamates are hydrolyzed to yield an alcohol, an amine, and carbon dioxide.
Ureides. Compounds that contain urea functionalities are stable and are not com-
monly metabolized or hydrolyzed.
Amines.An important metabolic route for primary and secondary amines is conjuga-
tion with either glucuronic acid or sulfuric acid to yield the corresponding water-soluble
glucuronides and sulfates. Another common reaction is dealkylation of secondary and
tertiary amines. The alkyl groups are sequentially removed and then “lost” as either
aldehydes or ketones. The amine is thus converted from a tertiary amine to a secondary
amine and then to a primary amine. This form of metabolism occurs most favorably if the
alkyl group is small, such as methyl, ethyl, or propyl. Finally, amines may be acetylated,
with the resulting amide undergoing typical amide metabolism.
Nitro.Typically, the nitro group is attached to an aromatic ring. Nitro groups are reduced
to the corresponding amine.
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 151