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324 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
TABLE 9-1.Examples of SARs That Affect the ADME of a Drug
Molecule
Specific Example Structural Change Effect on ADME SAR
Naproxen and
naproxen
sodium
Penicillin G and
penicillin G
benzathine
Simvastatin and
pravastatin
Quazepam and
temazepam
Fenofibrate and
fenofibric acid
Prednisolone and
prednisolone
sodium
phosphate
Beclomethasone
and
beclomethasone
diproprionate
Triamcinolone and
triamcinolone
acetonide
GI = gastrointestinal; IM = intramuscular; IV = intravenous.
Naproxen was
converted to its
inorganic sodium salt
Penicillin G was
converted to a lipidsoluble organic salt
Structural alterations
to increase the
water solubility of
pravastatin compared
with simvastatin
Temazepam contains a
hydrophilic hydroxyl
group not seen in
quazepam
Fenofibrate is a lipid-
soluble ester prodrug
of fenofibric acid
Prednisolone sodium
sulfate is a watersoluble ester prodrug
of prednisolone
Beclomethasone
diproprionate is
a lipid-soluble
ester prodrug of
beclomethasone
Hydroxyl groups are
converted to an
acetonide functional
group
Enhances the water
solubility and aqueous
dissolution of
naproxen
Decreases dissolution
and prolongs the
release from the
injection site
Increased water
solubility decreases
plasma protein
binding
The presence of the
hydroxyl group
allows it to undergo
direct glucuronide
conjugation without
any oxidative
metabolism
Enhances lipid solubility
and allows the drug
to pass through the GI
mucosal membrane
Enhances water
solubility and allows
the drug to be used as
an ophthalmic or IV
solution
Enhances lipid solubility
and allows the drug
to be better absorbed
within the pulmonary
tract or nasal cavity
Enhances lipid solubility
and allows for better
topical absorption
Converting drug molecules to
their inorganic salt forms can
enhance water solubility and
aqueous dissolution
Converting a drug molecule to a
lipid-soluble salt can enhance
its duration when given as an
IM injection
Within a class of drug molecules,
those that have a higher lipid
solubility tend to have higher
plasma protein binding
Within a class of drug molecules,
those that are more water
soluble tend to require less
metabolic transformations
than those that are more water
soluble
Converting a drug molecule
to its lipid-soluble ester can
enhance the absorption of
orally administered drug
molecules
Converting a drug molecule to
its water-soluble ester prodrug
form allows it to be formulated
as an ophthalmic or IV solution
Converting a drug molecule to
its lipid-soluble ester prodrug
form allows it to be formulated
as a pulmonary or nasal inhaler
Enhancing the lipid solubility of
a drug molecule allows it to
better penetrate the skin and
to be used as a topical cream or
ointment
present in a number of cephalosporins; however, once these adverse drug reactions were linked to
this functional group, most cephalosporins with the MTT functional group were discontinued.
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FIGURE 9-11.Sedating and nonsedating antihistamines.
Specific functional groups present on drug molecules within a class of drugs have also been
linked to drug interactions. As discussed in Chapter 6 and shown here in Figure 9-12, all tetracycline antibiotics contain a β-dicarbonyl group that can form chelates with calcium, magnesium,
aluminum, zinc, and iron in the gastrointestinal (GI) tract. These chelates have very poor water
solubility and can significantly decrease the absorption of tetracyclines. Preparations that contain
these metal ions (e.g., multivitamins, antacids, dairy products) can cause drug interactions if taken
concurrently with a tetracycline. This same type of drug interaction occurs with the fluoroquinolone
class of antibacterials, although the functional group present within a fluoroquinolone is slightly different than that found in the tetracycline. As shown in Figure 9-12, the quinolone carbonyl oxygen
and the carboxylic acid of ofloxacin can form a chelate with a metal ion and can cause a similar drug
interaction as observed with the tetracyclines. A key difference between these drug interactions and
the adverse drug reactions seen with captopril and MTT-containing cephalosporins is that the functional groups responsible for the drug interactions are also essential for the mechanisms of action of
tetracyclines and fluoroquinolones and cannot be replaced.
FIGURE 9-12.Chelation of metal ions with tetracyclines and fluoroquinolone antibiotics.
326 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Within a given class of drug molecules, the relative water/lipid solubility of the various drugs may
cause or prevent a particular drug interaction. As an example, let us consider the azole class of antifungal agents (Figure 9-13). As previously mentioned in Chapter 4, ketoconazole is highly lipid soluble, and its aqueous solubility depends on the ionization of the highlighted (boxed) imidazole ring.
Increases in gastric pH decrease the ionization of this basic functional group; therefore, its water solubility, dissolution, and absorption also decrease. As a result, patients requiring ketoconazole therapy
cannot take drugs that increase gastric pH such as H2 antagonists or proton pump inhibitors. This drug
interaction is not seen with all azole antifungal agents. Drugs such as fluconazole do not have as much
lipid character and do not rely as much on ionization for dissolution and oral absorption to occur. As
such, fluconazole does not have a pH dependent absorption and does not exhibit drug interactions
with either H2 antagonists or proton pump inhibitors. Please note that the imidazole ring of ketoconazole is more basic (pKa = 6.50) than the triazole rings of fluconazole (pKa = 1.76).
FIGURE 9-13.Ketoconazole and fluconazole.
Finally, the acid/base nature of a drug molecule is important in determining if it will be involved
in a plasma protein displacement interaction or not. This is a general SAR that was first discussed in
Chapter 3. Acidic drugs can bind to the plasma protein albumin through ionic interactions. Because
this binding is somewhat nonspecific, drug interactions can occur when two different acidic drug
molecules are competing for the same plasma protein binding site. The displacement of a drug from
its plasma protein allows more of the drug to be available to the blood and tissues. This increased
availability could affect the incidence of adverse drug reactions or the rate of metabolism/elimination of the drug. These drug interactions are clinically relevant for those acidic drugs that are more
than 90% plasma protein bound. Warfarin, NSAIDs, the sulfonylurea class of antidiabetic agents, and
phenytoin are examples of drugs and drug classes that are known to have drug interactions due to
plasma protein displacement interactions. All of these drugs or classes of drugs are acidic in character. Basic drugs bind to a different plasma protein, α
-acid glycoprotein, and, similarly to acidic drugs,
1
could cause plasma protein displacement interactions with other basic drugs competing for the same
binding sites. In general, plasma protein displacement interactions are seen much more with acidic
drug molecules than with basic drug molecules. Because acidic and basic drugs bind to two different
plasma proteins, acidic drugs do not cause displacement interactions with basic drugs and vice versa.
BASIC CONCEPTS IN MOLECULAR MODIFICATION
Lead compounds for drug development are often identified through natural product research, chemical alterations of known substrates and products of metabolic pathways, random screening of natural and synthetic molecules, de novo synthesis of compounds designed to interact with a specific
biological target, or via structural optimization of a specific adverse effect that is beneficial in the
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treatment of another disease state. The development of structural analogs can result in drug molecules that possess one or more of the following desired properties: enhanced potency and/or selectivity, a better balance of water and lipid solubility, improved absorption from the site of administration,
an optimal duration of action, decreased adverse drug events, and decreased drug interactions.
Molecular modification refers to the process of systematically altering the structure of a lead
compound that has a known chemical composition and biological activity. Two primary objectives
of this process are to tease out the pharmacophore of the lead compound and develop analogs that
could potentially provide more desirable chemical, pharmacological, and therapeutic properties as
well as a decrease in the incidence of adverse drug reactions. The term pharmacophore refers to the
minimum structural features that are required for pharmacological activity. The pharmacophore
includes essential functional groups and related chemical properties as well as stereochemical orientations. Inherent in this process is the establishment of SARs for the specific drug or drug class.
While an in-depth discussion of molecular modification and drug development is beyond the scope
of this text, the remainder of this chapter focuses on some of the most common types of modifications used to enhance the overall activity and physicochemical properties of a lead compound.
Conformational Restriction
Conformational restriction, discussed in Chapters 2 and 7, is used to lock in a desired conformation to
enhance the interaction of a drug molecule with its biological target and decrease interactions with
other receptors or biological targets responsible for adverse drug reactions. The SARs for the NSAIDs
and the 1,4-DHP class of calcium channel blockers discussed earlier in this chapter involve the use of
steric hindrance and provide examples of this concept (see Figure 9-7 and structures of diclofenac
and mefenamic acid).
Conformational restriction can also be achieved through the use of double bonds and the formation of geometric isomers. An example of this can be seen with the phenothiazine class of antipsychotic agents (Figure 9-14). This class of drugs produces their therapeutic actions by blocking
FIGURE 9-14.Chlorpromazine and conformationally restricted analogs.
328 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
dopamine action at the D2 receptor. The active conformation of chlorpromazine requires that the
aliphatic amine lies on the same side as the chlorine containing aromatic ring; however, conformational flexibility of this aliphatic chain allows the molecule to adopt a variety of inactive conformations. Evaluation of the structure of chlorprothixene reveals that a double bond has been inserted
into this aliphatic chain. This structural modification introduces conformational restriction and produces Z and E isomers. The Z isomer of chlorprothixene, in which the aliphatic chain is positioned
on the same side as the chlorine substituted aromatic ring, has much greater potency than the
E isomer. Further structural modifications yielded thiothixene, a clinically available drug. The Z isomer of thiothixene is much more potent than either the corresponding E isomer or the saturated
analog (i.e., the analog without the double bond).
Variation of Functional Groups
Addition, removal, and/or exchange of one functional group for another can alter the physicochemical characteristics, electronics, and the steric conformation of a drug molecule. This in turn can alter
the drug’s binding interactions, metabolism, and/or pharmacological effects (both beneficial and
detrimental). This type of molecular modification is quite common and is seen in many of the SAR
examples already provided (i.e., the addition of a methyl group to testosterone and the alteration
of the size of an N-alkyl group of adrenergic agonists). Described below are four additional examples
of this concept.
All angiotensin II receptor blockers (ARBs) are analogs of the general structure shown in
Figure 9-15. The highlighted (boxed) acidic functional group participates in an essential binding
interaction between the ARB and the angiotensin II AT1 receptor. This acidic functional group can be
FIGURE 9-15.Angiotensin II receptor blockers and the required acidic functional group.
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either a carboxylic acid, as seen in eprosartan and telmisartan, or a tetrazole, as seen in irbesartan.
All ARBs, with the exception of eprosartan and telmisartan, contain the tetrazole functional group.
Although a carboxylic acid meets the minimal structural requirements for ARB activity, it was found
that substitution of the carboxylic acid with a similarly acidic tetrazole provides a number of physicochemical and pharmacological advantages. The tetrazole is less likely to undergo metabolism,
is more lipophilic, enhances oral absorption, and allows for a better charge distribution than that
observed with analogs that contain a carboxylic acid. As discussed in Chapter 3, the negative charge
present at physiologic pH can be equally shared among all five atoms within a tetrazole (as compared with a carboxylic acid, which primarily shares the charge between the two oxygen atoms).
This enhanced charge distribution has been proposed to increase/improve the interaction of ARBs
with the AT1 receptor.
The sulfonylurea class of antidiabetic agents provides examples in which different variations
lead to different therapeutic advantages. The first generation of sulfonylureas, exemplified by tolbutamide and chlorpropamide in Figure 9-16, have small lipophilic functional groups located para to
the sulfonylurea group. The structure of tolbutamide contains a para methyl substituent that undergoes a rapid three-step oxidation to an inactive carboxylic acid metabolite. The half-life of tolbutamide ranges from 4.5 to 6.5 hours and must be administered two or three times daily. Substitution
of the para methyl substituent with a para chloro group, along with a smaller alkyl chain (by one
carbon atom), as found in chlorpropamide, extends the half-life of the drug to 36 hours. Unlike the
methyl group, the chloro group is electron withdrawing and is not subject to rapid oxidation. This
substituent deactivates the phenyl ring, so it limits the possibility of metabolic oxidation. Although
the extended duration of action allows for once daily dosing, this can produce more side effects
(e.g., hypoglycemia) than observed with tolbutamide. While these substitutions alter the duration
of action and the prevalence of an adverse effect, they don’t really enhance the binding of the sul-
+
fonamides to their target receptor, the ATP-sensitive K
channel. Replacement of the small lipophilic
functional groups with larger, more diverse functional groups resulted in second generation sulfonylureas, exemplified by glyburide in Figure 9-16. This larger group enhances drug binding interactions
with the target receptor and significantly increases the overall activity. Glyburide is between 50 and
FIGURE 9-16.A comparison of first and second generation sulfonylureas.
330 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
100 times more active than either tolbutamide or chlorpropamide. Although glyburide and other
second generation sulfonylureas have replaced tolbutamide and chlorpropamide in the treatment of
type 2 diabetes, these latter two drugs still serve as good examples of how molecular modification
can alter the duration of action of a drug molecule. Due to the rapid three-step oxidation described
in this example, para methyl groups are not present within the structure of many drug molecules.
Lincomycin (Figure 9-17) is a naturally occurring lincosamide antibiotic that inhibits bacterial protein synthesis. Replacement of the highlighted (boxed) hydroxyl group with a chloro group
as seen in clindamycin enhances the lipophilic character and imparts two important advantages.
Although lincomycin has poor oral absorption and is only administered via intramuscular (IM) injection, clindamycin has an oral absorption of approximately 90%. Additionally, this enhanced lipid
solubility allows clindamycin to better penetrate bacterial cell membranes and therefore achieve a
higher intracellular concentration than lincomycin.
FIGURE 9-17.A comparison of lincomycin and clindamycin.
Variation in functional groups can also convert a drug molecule from being a substrate for an
enzyme to an inhibitor of that enzyme. An example of this is seen with the antiviral drugs used to
inhibit reverse transcriptase, a viral enzyme required by the human immunodeficiency virus (HIV)
for replication. Shown in Figure 9-18 is the general mechanism by which polymerase enzymes add
nucleotide triphosphates to DNA or RNA. This mechanism requires two key structural features: a
nucleotide with a triphosphate at the 5′ position and a 3′ hydroxyl group on the growing (or newly
synthesized) DNA or RNA chain. The nucleic acid component of the nucleotide can vary but must
be able to appropriately pair with the template strand of DNA or RNA. The polymerase reaction
FIGURE 9-18.The mechanism of DNA and RNA polymerase enzymes (DNA sugars are shown).
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involves a nucleophilic attack by the 3′ hydroxyl group on the innermost phosphate of the nucleotide that will be added to the polymer. It should be noted that while this schematic depicts DNA
synthesis, RNA synthesis occurs via the same mechanism.
Zidovudine, abacavir, and lamivudine are reverse transcriptase inhibitors that are used to treat
HIV infections (Figure 9-19). These drugs are structural analogs of thymidine, guanidine, and cytidine, respectively. The key structural feature for all of these drugs is that the normal 3′ hydroxyl
group has been removed and replaced by a functional group that is not nucleophilic. The 5′ hydroxyl
groups have not been altered and can be converted to the active triphosphates. The triphosphate
forms of zidovudine, abacavir, and lamivudine can then be incorporated into DNA via the same
mechanism as shown in Figure 9-18. HIV synthesizes its DNA from RNA and uses a specific polymerase, reverse transcriptase, to catalyze this reaction. Because zidovudine, abacavir, and lamivudine
lack a 3′ hydroxyl group, the reverse transcriptase enzyme cannot add any additional nucleotides to
the growing strand of DNA, and the synthesis of HIV DNA is prematurely terminated. This action
inhibits reverse transcriptase and the production of new HIV particles. These effects are useful in
treating HIV infections.
FIGURE 9-19.HIV reverse transcriptase inhibitors. All drugs lack the required 3′ hydroxyl
group for HIV reverse transcriptase polymerization.
Zidovudine, abacavir, and lamivudine are examples of an antimetabolite, a drug that is structurally similar to an endogenous cellular metabolite but contains one or more structural modifications
that cause it to act as an inhibitor for a specific enzyme rather than a substrate. The sulfonamide
class of antibiotics previously discussed in this chapter is another example of an antimetabolite.
These drugs are structurally similar to PABA; however, replacement of the carboxylic acid found in
PABA with a similarly acidic sulfonamide functional group results in the inhibition of bacterial folic
acid biosynthesis.
Isosteres and Bioisosteres
The concept of isosteres was first proposed by Irving Langmuir in 1919. He defined isosteres as molecules or groups of atoms that have the same number and arrangement of electrons. According to
this definition, carbon monoxide and elemental nitrogen are isosteres, as are the anions azide and
cyanate.
332 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
This definition is rather limited and is not very applicable to drug molecules. In 1925, Grimm
expanded on Langmuir’s work and developed what is known as Grimm’s Hydride Displacement Law.
Grimm organized groups of atoms according to the number of valence electrons and allowed for the
fact that these groups may have a different number of atoms. According to Grimm, the addition of a
hydride (i.e., a hydrogen atom with its lone electron) to another atom results in a pseudoatom. Both
the pseudoatom and the atom having one more electron than the original atom have analogous
physical properties. Therefore, the addition of a hydride to a carbon atom would produce a CH pseudoatom. This pseudoatom would be expected to have analogous physical properties with a nitrogen
atom (i.e., the atom with one more electron than the original carbon atom). Using this concept,
Grimm constructed an initial list of isosteric functional groups (Table 9-2).
TABLE 9-2.Isosteres as Defined by Grimm’s Hydride Displacement
Law
4 5 6 7
C N O F
Valence Electrons
CH NH OH
CH
2
NH
CH
2
3
Examples of isosteric replacements are shown below with CH915, a hypothetical lead compound, and three of its analogs. Each analog contains one isosteric replacement of a single functional group. In Isostere A, an NH
group replaces a CH3 group. In Isostere B, a CH3 group replaces an
2
OH group, and in Isostere C, an oxygen atom replaces an NH group. Using the list of isosteric functional groups shown in Table 9-2, it is possible to draw other isosteric analogs of CH915.
Erlenmeyer used Grimm’s concept and expanded the definition of isosteres to include those
atoms, ions, or molecules that are identical in terms of the electrons present in their outer shell. This
allowed for the inclusion of several other atoms beyond Grimm’s initial work. A truncated list that
includes only those isosteres commonly found in drug molecules is shown in Table 9-3. In review-
ing this table, it should be evident that although there are some similarities, there are also some
significant differences among these isosteric groups. Depending on adjacent functional groups, N,
NH, and NH2 may be basic amines capable of undergoing ionization under physiologically relevant
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TABLE 9-3.Expanded Table of Isosteres According to Erlenmeyer
4 5 6 7
C N O F
+
N
Valence Electrons
conditions. In contrast, CH, CH2, CH3, O, OH, SH, and halogens are neutral functional groups and
are not ionized under physiologically relevant conditions. Additionally, N, NH, NH2, and OH tend
to enhance the overall water solubility of a compound while C, CH, CH2, CH3, and halogens tend to
enhance its overall lipid solubility. The SH group has a limited effect on water solubility. Differences
also exist among these isosteres in terms of electronegativity, steric size, and steric shape as well
as other physicochemical properties. In terms of molecular modification, it is important that these
differences be considered when evaluating the relative activities of isosteric molecules.
CH NH OH
P CH
2
S CH
NH
SH
Cl
Br
2
3
I
Application Question
Question: Evaluate the isosteric substitutions made to the hypothetical lead compound
CH915 and provide a summary of the key changes that could result from these structural
alterations.
Answer: In Isostere A, a neutral functional group (CH3) is isosterically replaced with a
basic functional group (NH2). The primary amine would be expected to be ionized in most
physiological environments and thus add to the overall water solubility of the isostere.
Additionally, because CH915 already has a secondary amine as part of its structure, the
addition of a primary amine may affect the pKa and the ionization of the secondary amine.
The presence of this second basic group may also allow an additional ionic bond or iondipole bond between Isostere A and its biological targets.
In Isostere B, a polar hydroxyl group is isosterically replaced with a more lipid-soluble
methyl group. This substitution enhances the overall lipid solubility of the compound. It
also results in the loss of a hydrogen bonding group, which may or may not be required for
the interaction of CH915 with its biological targets.
In Isostere C, a basic amine is isosterically replaced with an oxygen atom; hence, the
structure of this compound contains a neutral ether functional group instead of a basic
functional group. As such, Isostere C would be expected to be more lipid soluble than
CH915. Additionally, the binding interactions of these compounds with their biological targets may be significantly different. As discussed in Chapter 6, an ionic bond is often a key
recognition between a drug molecule and its biological target. The isosteric replacement of
a secondary amine with an ether oxygen atom would prevent this interaction.
Summary: The key point of this initial evaluation is to simply recognize the differences that
exist when an isosteric change is made. The ability to make these distinctions becomes
much more important whenever you are learning and evaluating the differences in activity
of specific drug molecules (or endogenous compounds) and their isosteres.
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