Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5323_Библиотеки_им_академика_М_И_Перельмана
.pdf
254 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-8.Examples of benzylic oxidation catalyzed by CYP450 enzymes.
FIGURE 8-9.Examples of allylic oxidation catalyzed by CYP450 enzymes.
introduce a hydroxyl group into the structure of the drug molecule. Examples of these are shown in
Figure 8-10. Oxidation of flurazepam occurs at the C3 position of the benzodiazepine ring system.
Although this C3 carbon atom is adjacent to the imine nitrogen (a heteroatom), this is one exception
in which the resulting hydroxyl group is stable. Additionally, this carbon atom is adjacent to both
an imine and a carbonyl group and is highly activated for oxidation. Oxidation of benzodiazepines at
this position represents a major route of metabolism for this class of drug molecules. In general, the
CH 8 - DRUG METABOLISM 255
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 8-10.Examples of CYP450 catalyzed oxidation of carbon atoms adjacent to
imines and carbonyl groups.
hydroxylation of a carbon atom directly adjacent to a single carbonyl group is not a major route of
drug metabolism; however, an example of this is seen with aminoglutethimide.
Please note that in all examples shown in Figures 8-8 to 8-10, the carbon atoms were prochiral;
thus, the oxidation of these atoms generated a new chiral center. Although this does not always
occur, it is quite common. It many cases, only one stereoisomer is formed.
Application Question
Shown below is the structure of pentazocine. This drug molecule contains five allylic and
benzylic carbon atoms. Evaluate these five potential oxidation sites and identify the carbon
atoms that are most likely to be oxidized.
256 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Answer: Allylic carbon atoms 2 and 3 are the least sterically hindered and, thus, are the most
likely to undergo oxidation. Furthermore, these two carbon atoms are not identical. Allylic
carbon atom 2 is located on the same side of the double bond as a methylene carbon, while
allylic carbon atom 3 is located on the same side of the double bond as a hydrogen atom. As
such, the oxidation of allylic carbon atom 2 is more sterically hindered than the oxidation
of allylic carbon atom 3. The oxidation of allylic carbon atom 3 to a primary hydroxyl group
is the major metabolic pathway for pentazocine. Allylic carbon atom 1 and benzylic carbon
atom 1 are much more sterically hindered than allylic carbon atoms 2 and 3 and are much less
likely to undergo oxidation. Additionally, allylic carbon atom 1 is attached to a heteroatom. If
oxidation did occur at this site, the initial metabolite would be unstable and not result in the
formation of a hydroxyl group. Benzylic carbon 2 lacks a hydrogen atom and thus does not
meet the criteria for CYP450 oxidation.
Oxidation of Aliphatic and Alicyclic Carbon Atoms
Aliphatic carbon chains can undergo oxidation at either the terminal methyl group in the chain or
at the penultimate (i.e., next to last) carbon atom in the chain. The locations of these carbon atoms
are also known as the omega (ω) and omega-1 (ω-1) positions, and these oxidations are commonly
referred to as ω oxidation and ω-1 oxidation. Examples are shown in Figure 8-11. Please note that
FIGURE 8-11.Examples of v oxidation and v-1 oxidation catalyzed by CYP450 enzymes.
CH 8 - DRUG METABOLISM 257
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
while both ω and ω-1 oxidations are often available for drug molecules with alkyl chains, in most
cases oxidation would only need to occur at one of these positions to appropriately enhance water
solubility and/or provide a functional group that could undergo Phase II conjugation. This is another
reminder that drug metabolism occurs in an efficient manner and uses the least number of steps
necessary to eliminate and/or deactivate the drug molecule.
Monosubstituted alicyclic rings and nonaromatic heterocyclic rings can also undergo oxidation. Similar to aromatic oxidation, these rings tend to be oxidized at the least sterically hindered
positions. For cyclohexane rings, oxidation generally occurs at the C3 or C4 position, as seen with
dicyclomine in Figure 8-12. Please note that due to the electronic nature of an aromatic ring, the C3
position of a cyclohexane is not the same as the meta position of a phenyl ring. As such, oxidation
at the C3 position of cyclohexane ring is more likely to undergo oxidation than is the meta position
of a phenyl ring. Five- and seven-membered nonaromatic rings can also undergo this type of oxidation, as seen with the cyclopentane ring of penbutolol and the hexahydroazepine ring of tolazamide.
As shown in Figure 8-12, the oxidations occur at either the C
or C4 positions of these rings because
3
these carbon atoms are the least sterically hindered. With one exception, all of these oxidations
occur at prochiral carbon atoms. Due to its symmetrical nature, the C4 position of dicyclomine is not
a prochiral center. Due to their alicyclic or nonaromatic heterocyclic nature, oxidation at the C3 or C4
positions can produce cis and trans geometric isomers.
FIGURE 8-12.Examples of CYP450 catalyzed hydroxylation of nonaromatic rings.
258 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Oxidation of Amines, Amides, and Aromatic Nitrogen Atoms
Three major oxidative transformations are available for amines and amides: oxidative deamination,
oxidative N-dealkylation, and N-oxidation. The specific transformation often depends on the nature
of other functional groups attached to the nitrogen atom. Primary, secondary, and tertiary amines
are often metabolized differently, as shown in the examples below. The primary route of oxidative metabolism for aromatic nitrogen atoms is N-oxidation because they cannot undergo oxidative deamination or oxidative N-dealkylation. Quaternary heterocyclic nitrogen atoms can undergo
N-dealkylation but not oxidative deamination or N-oxidation.
Oxidative Deamination
This metabolic transformation primarily occurs with primary amines; however, there is some evidence that it can also occur with secondary amines. For oxidative deamination to occur, the
α-carbon (i.e., the carbon atom directly adjacent to the nitrogen atom) must be attached to at least
one hydrogen atom. The general mechanism of oxidative deamination is shown below.
In this mechanism, the carbon atom that is α to the amine undergoes oxidation. The resulting
intermediate is known as a carbinolamine because the α-carbon atom is now attached to both a
hydroxyl (i.e., alcohol) group and an amine. Carbinolamines are unstable intermediates and undergo
a further reaction to generate either an aldehyde or ketone, depending on whether the R1 group is a
hydrogen atom or a carbon atom, respectively. This reaction causes the release of ammonia or a primary amine, depending on whether the R2 group is a hydrogen atom or a carbon atom, respectively.
Examples of drugs that can undergo oxidative deamination are shown in Figure 8-13. In looking at
these examples, please note that the primary or secondary amine is removed and that the resulting
metabolite retains the remaining portion of the drug molecule.
Oxidative N-Dealkylation
This metabolic transformation can occur with secondary or tertiary amines or amides. The mechanism of oxidative N-dealkylation (henceforth denoted simply as N-dealkylation) is very similar
to oxidative deamination. As shown below, the alkyl group initially undergoes oxidation to form
a carbinolamine. The carbinolamine then undergoes a reaction leading to the formation of an
N-dealkylated drug molecule and either an aldehyde (shown below) or a ketone, depending on the
alkyl group that is removed. Similar to oxidative deamination, the removed alkyl group must contain
a hydrogen atom. N-Dealkylation of tertiary amines produces secondary amines, and N-dealkylation
of secondary amines produces primary amines.
Although oxidative deamination and N-dealkylation are similar, there is a distinct difference
between these two metabolic transformations. In oxidative deamination, a carbon atom is oxidized to an aldehyde or ketone and the nitrogen atom leaves as ammonia or a primary amine.
CH 8 - DRUG METABOLISM 259
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 8-13.Examples of oxidative deamination catalyzed by CYP450 enzymes.
As mentioned above, the metabolite no longer contains the nitrogen atom and is composed of the
remainder of the drug molecule. In N-dealkylation, an alkyl group is oxidized and removed from
the drug molecule. The metabolite still contains the nitrogen atom as well as the remainder of the
drug molecule. To prevent any confusion between these metabolic processes, readers are highly
encouraged to compare the examples in Figure 8-13 and those shown below and take advantage of
the fact that deamination literally means that an amine is removed from the drug molecule and that
dealkylation literally means that an alkyl group is removed from the drug molecule.
In general, smaller alkyl groups are more likely to undergo N-dealkylation than are larger
groups. Examples of alkyl groups known to undergo this type of metabolic transformation include
methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, and benzyl groups. Due
to the lack of a hydrogen atom, functional groups such as a t-butyl group cannot be removed by
N-dealkylation.
Examples of two drugs that are known to undergo N-dealkylation are shown in Figure 8-14. The
functional groups on meperidine, a tertiary amine, and diazepam, an amide, that can be dealkylated
have been highlighted.
260 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-14.Examples of drug molecules that can undergo CYP catalyzed oxidative
N
-dealkylation.
There are four key points regarding drug molecules and N-dealkylation.
1. Whenever a tertiary amine contains two different alkyl groups, as seen with nicardipine, the
smaller alkyl group is almost always removed before the larger group.
Nicardipine is also useful in reinforcing a previous concept. As shown in its structure, the larger
alkyl group contains a benzylic carbon atom that is attached to a heteroatom. As previously discussed, this benzylic carbon atom can undergo oxidation; however, it does not produce a stable secondary hydroxyl group. Oxidation of this benzylic carbon atom forms a carbinolamine that collapses
and forms an N-dealkylated metabolite. Thus, oxidation at this carbon atom is correctly described
as N-dealkylation and not benzylic oxidation.
2. As exemplified by atenolol, drug molecules that contain secondary amines can directly
undergo oxidative deamination or initially undergo N-dealkylation. In these situations,
oxidative deamination is normally a minor metabolic pathway, and N-dealkylation is normally the major pathway.
CH 8 - DRUG METABOLISM 261
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
3. Secondary and tertiary amines located in the middle of a drug molecule and attached to
large alkyl chains are less likely to undergo N-dealkylation. This is illustrated with salmeterol and is an example of a previously noted concept. Functional groups that are sterically
hindered or otherwise difficult to access are much less likely to be metabolized than those
that are easily accessible. In terms of salmeterol, aromatic oxidation and benzylic oxidation
are less sterically hindered than is dealkylation of the large alkyl chain.
4. As illustrated in Figure 8-15, amitriptyline can undergo two N-dealkylations and an oxidative deamination. Similar to atenolol, once the first methyl group is dealkylated, the
resulting secondary amine could directly undergo oxidative deamination. Returning to a
previously discussed concept, the human body uses only the minimum number of these
transformations that it needs to enhance the water solubility of the drug and allow for its
excretion. For some drug molecules, all of these steps are required; for others, perhaps only
one or two.
Secondary and tertiary alicyclic amines can form lactones, as illustrated with niacin (aka nicotinic acid) in Figure 8-16. Oxidation of the alicyclic carbon atom adjacent to the tertiary nitrogen
produces a carbinolamine. The carbinolamine subsequently breaks down to form a secondary amine
and an aldehyde similar to what was seen with oxidative deamination and N-dealkylation; however,
because this metabolic transformation began with an alicyclic ring, both functional groups remain
as part of the initial metabolite. As discussed later in this chapter, aldehydes can be further oxidized
to carboxylic acids. Because the secondary amine is close to this newly formed carboxylic acid, the
functional groups can combine using a condensation reaction to form a lactone. The methyl group
can be removed via N-dealkylation either prior to or after lactone formation. Lactone formation
does not always occur with alicyclic amines; however, it should be considered as a possible metabolic pathway.
262 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-15.Possible metabolic pathways for amitriptyline.
FIGURE 8-16.Formation of a lactone metabolite of niacin.
N-Oxidation
Unlike oxidative deamination and N-dealkylation, N-oxidation involves a direct oxidation of the
nitrogen atom as opposed to an adjacent carbon atom. Although it is not necessary for an adjacent
carbon atom to be attached to a hydrogen atom, the products of N-oxidation vary based on the
presence or absence of a hydrogen atom. N-Oxidation of secondary and tertiary amines can be
CH 8 - DRUG METABOLISM 263
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
catalyzed by either CYP450 or FMO enzymes whereas N-oxidation of primary amines is almost
always catalyzed by CYP450 enzymes.
Primary amines that are attached to a carbon atom that lacks a hydrogen atom can be sequentially oxidized to hydroxylamines and nitroso groups. Overall, only a few drugs have this structural
feature. An example is seen below with the antiviral agent amantadine. Oxidative deamination is
not possible for amantadine; however, N-oxidation can occur.
The carbon atom adjacent to most primary amines is normally attached to at least one hydrogen atom. Although oxidative deamination is the most likely metabolic transformation for a primary amine, it can also be directly oxidized to sequentially form hydroxylamines, imines, oximes,
and aldehydes. An example is shown in Figure 8-17 with primaquine. Please note that the aldehyde metabolite resulting from hydrolysis of the imine is the exact same metabolite that would be
formed if primaquine were directly metabolized by oxidative deamination. The oxime metabolite is
a tautomeric form of the nitroso group seen with amantadine.
FIGURE 8-17.CYP450 catalyzed
N
-oxidation of the primary amine of primaquine.
Соседние файлы в папке Библиотека им академика М.И. Перельмана