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
334 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
In 1951, Friedman applied the concepts developed by Grimm and Erlenmeyer to biological systems and introduced the term bioisostere. According to Friedman, bioisosteres are functional groups
or molecules that have similar chemical and physical properties that produce broadly similar biological properties. The latter part of this definition allows for bioisosteres to produce either similar or
opposite actions within the same biological system. As such, a bioisosteric substitution can enhance
the activity of a given agonist or antagonist or it can result in the conversion of an agonist to an antagonist. Similarly, a bioisosteric substitution can convert a molecule from being an enzyme substrate
to an enzyme inhibitor. In terms of the molecular modification of drug molecules, the terms isosteric
replacement and bioisosteric replacement are commonly used interchangeably; however, there is a
subtle difference. Because it is not possible to know a priori if a given structural change in a drug molecule will result in the retention of biological activity, the term isosteric replacement is appropriate
to describe the change in functional groups. Once it is determined that this isosteric change resulted
in the retention of biological activity, then the term bioisosteric replacement becomes appropriate
to use. As an example, it is appropriate to state that isosteric replacements of the functional groups
present in CH915 resulted in the formation of Isosteres A, B, and C because all of these compounds
are hypothetical and have not actually been tested for biological activity. Until biological activity has
been determined, it is inappropriate to use the term bioisosteric replacement for these compounds.
Over the years, the definition of an isostere or a bioisostere has been expanded to include
functional groups that have a similar distribution and location of electron density and that have a
similar size and shape. This led to the establishment of two categories of isosteres: classical isosteres
and nonclassical isosteres.
Classic Isosteres
Classic isosteres are those that follow Grimm and Erlenmeyer’s original definitions (Table 9-4). The
isosteres have been organized according to their valence (i.e., the number of bonds in which they can
participate). Within each subclassification, any one functional group can be used in place of another.
Also included in Table 9-4 is a list of aromatic ring equivalents, otherwise known as annular equiva-
lents. Some of these are simply isosteric replacements of trivalent atoms (e.g., benzene to pyridine)
whereas others result from the replacement of the -C=C- group in benzene with either a nitrogen,
oxygen, or sulfur atom. Additional isosteric replacements of trivalent atoms result in imidazole,
isoxazole, and other five-membered heterocyclic rings.
TABLE 9-4.Classic Isosteres
Monovalent isosteres H, CH3, NH2, OH, F, Cl, SH, Br, I
Divalent isosteres (single bonds) -CH2-, -NH-, -O-, -S-
Divalent isosteres (double bonds) C=O, C=NH, C=S
Trivalent isosteres -C=, -N =, -P=
Tetra-substituted atoms =C=, = N+=, = P+=
Annular equivalents (aromatic ring substitutions)
Classic isosteric and bioisosteric replacements are nothing more than structural variations of functional groups, as exemplified with two of the examples in the previous section. The
isosteric replacement of the methyl substituent in tolbutamide with a chloro group resulted in the
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 335
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
formation of chlorpropamide, a bioisostere with decreased metabolism and a longer duration of
action. Similarly, the isosteric replacement of the hydroxyl group within lincomycin with a chloro
group resulted in the formation of clindamycin, a bioisostere with improved oral bioavailability and
enhanced bacterial penetration. Procainamide, 6-mercaptopurine, and acetazolamide provide three
additional examples of classical bioisosteric replacements.
Procaine (Figure 9-20) is a local anesthetic used in a variety of outpatient procedures. Its
pharmacological actions are the result of a decrease in sodium permeability in nerve membranes,
a mechanism that is also useful in the treatment of arrhythmias. Due to rapid ester hydrolysis,
procaine has poor oral bioavailability and a relatively short duration of action. As such, it cannot be
used as an antiarrhythmic agent. An isosteric substitution of the ester oxygen atom of procaine with
a nitrogen atom results in the formation of procainamide. This bioisostere is less likely to undergo
hydrolysis and, as a result, has an oral absorption of 80% to 90% and a longer duration of action.
Although procainamide’s role in the treatment of arrhythmias has significantly decreased over the
last several decades, it is still a good example of how an isosteric replacement can convert a drug
that cannot be administered orally into one that can.
FIGURE 9-20.Procaine and procainamide.
Hypoxanthine is an endogenous compound that is readily converted to inosine monophosphate, a key intermediate in the biosynthesis of both adenosine monophosphate (AMP) and guanosine monophosphate (GMP) (Figure 9-21). An isosteric replacement of the OH group with an SH
group results in the formation of 6-mercaptopurine, an antimetabolite of hypoxanthine. Similar
to hypoxanthine, 6-mercaptopurine can react with 5-phosphoribosyl 1-pyrophosphate (PRPP) to
form thio-inosine monophosphate (T-IMP). Once this occurs, T-IMP acts in a competitive fashion
to inhibit the conversion of IMP to AMP and GMP. This action is useful in the treatment of acute
lymphocytic leukemia.
As shown in Figure 9-22, the enzyme carbonic anhydrase catalyzes the hydration of CO
to
2
carbonic acid as well as the reverse reaction. This action is important for the reabsorption of sodium
bicarbonate from the renal tubules, transport of CO2 from various tissues to the lung, and formation
of aqueous humor in the eye. Inhibitors of this enzyme all contain a sulfonamide functional group
in which the nitrogen atom is unsubstituted (e.g., acetazolamide). The unsubstituted sulfonamide
group is bioisosteric with carbonic acid. More specifically, the SO2 group is isosteric with CO2, and
the NH2 group is isosteric with the OH group. Inhibitors of carbonic anhydrase are therapeutically
useful in the treatment of glaucoma and ocular hypertension.
Nonclassical Isosteres
Nonclassical isosteres are those that do not follow Grimm and Erlenmeyer’s guidelines. They are
often larger in size, rarely have the same number of atoms or pseudoatoms, and can vary substantially in terms of valence electrons. Although this theoretically allows for a more diverse variation
of isosteric functional groups, it should be noted that there are many more examples of clinically
approved drugs that contain classical bioisosteres than clinically approved drugs that contain nonclassical bioisosteres. A representative list of nonclassical isosteres is shown in Table 9-5.
As previously discussed with the ARB class of antihypertensive agents, tetrazoles are bioisosteric replacements for carboxylic acids and provide a number of physicochemical and pharmacological advantages. Histamine H2 receptor antagonists are another example of the use of nonclassical
336 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 9-21.The formation of GMP and AMP from hypoxanthine and the inhibition by
the antimetabolite, 6-mercaptopurine (PRPP = 5-phosphoribosyl 1-pyrophosphate).
bioisosteres. One of the first drug molecules evaluated in clinical studies was metiamide. As seen in
Figure 9-23, metiamide contains a thiourea functional group as part of its structure. Although this
compound was successful in selectively blocking the histamine H2 receptor, clinical trials revealed
that it produced agranulocytosis in a significant number of patients. This adverse effect was subsequently linked to the presence of the thiourea functional group. Cimetidine, the first H2 receptor
antagonist approved by the Food and Drug Administration (FDA), contains a nonclassical bioisosteric
replacement of the thiourea group. From a chemical perspective, this nonclassical bioisostere is similar to thiourea in that it is a polar, nonbasic, nitrogen-containing functional group. Development of
ranitidine and nizatidine included a different nonclassical bioisostere for the thiourea group as well
as a few other structural alterations, including the use of annular equivalents.
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 337
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 9-22.Carbonic anhydrase and its inhibition by sulfonamide (see boxes).
TABLE 9-5.Nonclassical Isosteres
Original Functional Group Bioisosteres
Halogens (F, Cl, Br, I) CF3 (Trifluoromethyl) CN (Nitrile)
FIGURE 9-23.H
receptor antagonists as examples of nonclassical bioisosteres.
2
338 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Homologation
Homologation refers to the process of successively adding methylene groups (CH2) to a hydrocarbon
chain. A simple example of this concept is shown below (see boxes). The original methyl substituent
can be successively lengthened to produce an ethyl homolog, an n-propyl homolog, and an n-butyl
homolog. Methylene groups can also be added to create branch points, as seen with the isopropyl
and t-butyl homologs. Homologation successively increases the overall size of the functional group
as well as its lipophilic character.
This type of molecular modification can be used to investigate the steric dimensions of a drug
molecule’s biological target(s), enhance the lipid solubility of the drug molecule, and optimize the
binding interactions between the drug molecule and its biological target(s). Additionally, homologation can be used to enhance the selectivity of a drug molecule for a specific biological target.
An example of this concept was previously discussed with the adrenergic agonists in Figure 9-5.
Epinephrine nonselectively binds to both α- and β-adrenergic receptors. Homologation of the
methyl group to an isopropyl group produces a selective β-adrenergic agonist. This selectivity is due
to the fact that the β-adrenergic receptors contain a larger hydrophobic binding pocket than the α
receptors. Further homologation to a t-butyl group provides a selective β2 receptor agonist for the
exact same reason. The β2 receptor has room to accommodate a larger and bulkier N-substituent
as compared with the β1 receptor. This last point is further exemplified with salmeterol, a longacting, selective β2 receptor agonist used for the treatment of asthma and COPD. The large alkyl
chain and phenyl ring represent homologs of the original methyl group seen within the structure of
epinephrine.
Homologation can also be used to convert an agonist at a specific receptor to an antagonist at
that same receptor. Some biological targets (primarily protein receptors) contain auxiliary or accessory binding sites that are located directly adjacent to the active/required binding site. When an
agonist binds to the receptor, these auxiliary sites are often unoccupied or only partly occupied, and
the agonist produces its normal response. This response often requires a specific conformational
change that triggers a cascade of events that may include intracellular signal transduction, second
messenger production, gene regulation, and/or the opening of an ion channel. Drug homologation
allows the resulting analog to bind to both the normal agonist site as well as to an auxiliary site.
Occupation of the auxiliary site by the drug analog can cause the receptor to adopt an altered conformation that is not able to trigger this cascade of events. As such, agonist activity is blocked, and
the homolog acts as an antagonist. An example is seen with the opioid analgesics (Figure 9-24).
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 339
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 9-24.Morphine and its
Homologation of the methyl group of morphine to a propyl group, a cyclobutylmethyl group, or
an allyl group produces a drug that acts as an antagonist at the opioid µ receptor. Although the
cyclobutylmethyl group is technically not a homolog due to the presence of a ring structure, it is
sufficiently similar to homologs in that it is larger than the methyl group present on morphine. The
allyl group is simply an unsaturated analog of the propyl group.
The addition of large, lipophilic functional groups to a drug molecule is a type of molecular
modification that is similar to homologation. It is primarily used to convert agonists to antagonists
through the addition of hydrocarbon chains and rings that can interact with auxiliary or accessory
binding sites present on specific receptors. The primary difference is that the structural additions are
not limited to the successive lengthening or branching of a hydrocarbon chain. Muscarinic antagonists, commonly referred to as anticholinergic agents, provide good examples. As illustrated in
Figure 9-25, the major chemical difference between acetylcholine and dicyclomine and propantheline is the presence of aromatic and/or aliphatic rings that have been added to the terminal methyl
group of acetylcholine. The boxed sections of dicyclomine and propantheline can structurally mimic
acetylcholine when evaluated on an atom-by-atom basis. Both of these drugs can bind to the muscarinic receptor and inhibit the action of acetylcholine.
n
-propyl, cyclobutylmethyl, and allyl homologs.
Chain Branching
This type of molecular modification is less common than those previously described and often
involves either the insertion of a methyl group into an unbranched alkyl chain or the movement of a
functional group to change an unbranched alkyl chain into a branched alkyl chain. This type of structural modification can create a new chiral center and therefore can alter both the size of the alkyl
chain and the orientation of other functional groups. As with homologation-based modifications,
the addition of a hydrocarbon branch to an alkyl chain may enhance the overall lipid solubility of the
drug molecule, alter the selectivity of a drug molecule for a specific biological target, and decrease
the metabolism of a drug molecule.
Within the phenothiazine class, some drugs can be used as antipsychotic agents to treat schizophrenia and other psychotic disorders while others can be used as antihistamines to treat pruritus
and motion sickness. The antipsychotic effects are due to the blockade of dopamine D2 receptors,
340 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 9-25.Acetylcholine and anticholinergic agents (boxed portions of the structures
mimic acetylcholine).
whereas the antihistamine effects are due to the blockade of peripheral histamine H1 receptors. For
a phenothiazine to interact with the dopamine D2 receptor, it must contain an electron withdrawing group attached to the phenothiazine ring, and it must have an unbranched three-carbon chain
that separates the phenothiazine nitrogen atom and the side chain amine. Removal of the electron
withdrawing group and addition of a branch in the alkyl chain significantly decreases dopamine D2
receptor binding and enhances interaction with the histamine H1 receptor binding. Examples are
shown in Figure 9-26.
FIGURE 9-26.Phenothiazines with unbranched and branched alkyl chains.
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 341
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
The isosteric conversion of procaine to the orally active antiarrhythmic agent procainamide
was discussed earlier in this chapter. Lidocaine is similar to procaine in several respects. It possesses both local anesthetic and antiarrhythmic properties, undergoes rapid metabolism (half-life
of 15-30 minutes), has a short duration of action, and cannot be administered orally. When administered intravenously (IV), lidocaine initially undergoes oxidative N-dealkylation to yield an active
metabolite, monoethylglycinexylidide. Subsequent amide hydrolysis causes this metabolite to
be inactive (Figure 9-27). Because lidocaine already contains an amide group, it was not possible
to impart oral activity by using the same molecular modification as seen with procaine; however,
the use of chain branching was successful in meeting this goal. Tocainide is an α-methyl analog of
monoethylglycinexylidide. The α-methyl group provides a branch in the alkyl chain between the
amide carbonyl group and the primary amine. This α-methyl group provides sufficient steric hindrance to amide hydrolysis and allows tocainide to be used orally. Unlike lidocaine, tocainide is
slowly metabolized and has a half-life of 12 hours.
FIGURE 9-27.Lidocaine and tocainide.
The Conversion of an Active Drug to a Prodrug
In this type of molecular modification, an active drug molecule is altered to produce an inactive or
significantly less active analog known as a prodrug. Upon therapeutic administration, the prodrug is
converted in vivo to the active drug molecule by one or more of the metabolic transformations that
were discussed in Chapter 8. This metabolic conversion is known as bioactivation.
The most common type of prodrug modification is the conversion of hydroxyl groups or carboxylic acids to either water- or lipid-soluble esters. Esterases are ubiquitous within the human body
342 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
and can easily convert this type of prodrug to the corresponding active drug molecule. Examples of
this concept along with their physicochemical advantages were discussed in Chapters 5 and 8 and
have been summarized in Table 9-6. Two additional examples of ester prodrugs are presented here.
TABLE 9-6.Advantages of the Use of Water- and Lipid-Prodrug Esters
Water-Soluble Prodrug Esters
Advantage Example
Allow for the preparation of concentrated
ophthalmic solutions
Allow for the preparation of concentrated IV
solutions
Lipid-Soluble Prodrug Esters
Advantage Example
Enhance oral absorption Fenofibrate, candesartan cilexitil (Chapter 5);
Allow for the preparation of IM or subcutaneous
depot injections
Enhance the palatability of oral suspensions Clindamycin palmitate (Chapter 9)
Enhance the absorption of drugs that are
administered via oral or nasal inhalation
Enhance the absorption of drugs that are
administered as topical creams or ointments
Prednisolone sodium phosphate (Chapter 5)
Chloramphenicol sodium succinate (Chapter 5);
fosphenytoin (Chapter 9)
perindopril, valacyclovir, oseltamivir, diphenoxylate
(Chapter 8)
Haloperidol decanoate, estradiol valerate (Chapter 5)
Beclomethasone dipropionate (Chapter 5)
Hydrocortisone butyrate (Chapter 5)
Phenytoin is an antiepileptic agent used to treat status epilepticus, partial seizures, and tonicclonic seizures. Although it can be administered orally or parenterally, there are a number of limitations with its parenteral use. Phenytoin is compatible with normal saline but not 5% dextrose
or Lactated Ringer’s solution (two standard IV solutions). Additionally, it should not be administered by the IM route due to erratic absorption and well-documented tissue damage. Fosphenytoin
(Figure 9-28) is a more water-soluble prodrug of phenytoin. It is compatible with all standard IV
solutions, can be administered by the IM route, has fewer adverse reactions at the site of administration, and can be given at a faster rate. After administration, fosphenytoin undergoes a two-step
bioactivation process. Hydrolysis of the phosphate group produces an unstable carbinolamine similar to that produced during oxidative deamination and oxidative N-dealkylation. The carbinolamine
then collapses (as discussed in Chapter 8) to release formaldehyde and phenytoin.
Clindamycin is an antibiotic used to treat a variety of infections, including those located in the
lower respiratory tract and the intra-abdominal region. Similar to many other antibiotics, clindamycin has a bitter taste that prevents administration as an oral solution for children as well as for
patients who have difficulty swallowing tablets or capsules. To increase the palatability of clindamycin, it was modified to a lipid-soluble palmitate ester (Figure 9-29) and formulated as a suspension. In this formulation, the palmitate ester does not dissolve in the saliva. The patient tastes the
water-soluble flavoring normally added to these suspensions and does not detect the bitter tasting
drug. This is similar to the lipid-soluble stearate salt of erythromycin discussed in Chapter 5. The key
difference between these two examples is that the palmitate ester prodrug requires in vivo hydrolysis to release clindamycin while salts simply need to dissociate.
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 343
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 9-28.Metabolic conversion of the prodrug, fosphenytoin, to the active drug,
phenytoin.
FIGURE 9-29.Clindamycin and its lipid-soluble palmitate prodrug.
Although water- and lipid-soluble esters are the most common types of prodrugs, other hydrolysable functional groups, such as amides and carbamates, have been used to develop prodrugs
with distinct therapeutic benefits. Additionally, metabolic activation by mechanisms other than
hydrolysis has led to the development of prodrugs with specific advantages beyond those that can
be achieved by altering the water or lipid solubility of a drug molecule. Seven examples are provided
below. The first three examples illustrate the usefulness of amide and carbamate prodrugs and the
other four examples illustrate prodrugs that are activated by mechanisms other than hydrolysis.
Interferon alfa-2a and alfa-2b are drugs used in the treatment of hepatitis B and hepatitis C infections. They are similar to naturally occurring interferon and provide an antiviral effect by enhancing
the production and/or release of specific enzymes that inhibit viral replication. To enhance their
duration of action and thus require less frequent subcutaneous injections, these drugs can be converted to polyethylene glycol (PEG) prodrugs, or pegylated interferons. The PEG chain is linked to
lysine residues present on interferon alfa-2a and alfa-2b. Hydrolysis of the resulting amide releases
Соседние файлы в папке Библиотека им академика М.И. Перельмана