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314 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
features that enhance activity. In this section, we review the SAR required for three different classes
of drugs.
The first example revisits the sulfonamide class of antibiotics discussed above. This class of
drugs mimics PABA due to the presence of similar functional groups. As shown in Figure 9-1, PABA
contains a primary aromatic amine and an ionizable carboxylic acid that are located para to one
another. Thus, sulfonamides, as exemplified by sulfisoxazole, must have a primary aromatic amine
and an ionized sulfonamide located para to one another. Sulfanilamide and sulfamethoxazole,
shown above, also meet these structural requirements, and any alterations to these functional
groups eliminate or greatly decrease the antibacterial action.
FIGURE 9-1.PABA and sulfisoxazole.
A second example revisits the mechanism of the β-lactam class of antibiotics that was introduced
in Chapter 6. This class of drugs exerts their antibacterial action via inhibition of the cross-linking
of bacterial cell walls. Specifically, they bind to the bacterial enzyme transpeptidase, irreversibly
acylate the enzyme, and prevent newly formed peptidoglycan strands from cross-linking. The mechanism catalyzed by transpeptidase involves the initial cleavage of a -Ala--Ala bond that is present
on a newly synthesized peptidoglycan strand. As shown in Figure 9-2, a β-lactam antibiotic can
perfectly mimic the -Ala--Ala sequence found within the peptidoglycan. From a mechanistic perspective as well as an SAR perspective, all active β-lactams must contain an ionized carboxylic acid
and an intact β-lactam ring to effectively mimic -Ala--Ala and inhibit transpeptidase.
FIGURE 9-2.A structural comparison of d-Ala-d-Ala and a a-lactam antibiotic.
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Some bacterial organisms produce an enzyme known as β-lactamase. This enzyme catalyzes the
cleavage of the β-lactam bond found within the structure of a penicillin or cephalosporin. Because
cleavage of this bond destroys the required SAR for transpeptidase inhibition, the presence of this
enzyme allows the bacteria to be resistant to certain β-lactam antibiotics. As mentioned in Chapter 2,
strategically placed functional groups can provide steric hindrance and prevent β-lactamase from
inactivating the β-lactam antibiotic. The steric hindrance found within this class of agents is provided by either a methyl group or a methoxy group that is either directly adjacent to or oriented
in the direction of the β-lactam carbonyl group. Examples of specific drugs with these structural
features are shown in Figure 9-3. Although this steric hindrance confers β-lactamase resistance,
it does not interfere with the binding of the β-lactam to transpeptidase. The presence or absence
of this structural feature determines whether a β-lactam antibiotic is susceptible or resistant to
β-lactamase and thus provides another SAR for this class of drugs.
FIGURE 9-3.Examples of a-lactam antibiotics with functional groups that sterically
prevent the binding of a-lactamase.
The final example of SARs and pharmacological activity involves inhibitors of the enzyme
3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase. This enzyme catalyzes the conversion of
HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Inhibitors of this
enzyme have been developed for use in the treatment of hypercholesterolemia and other dyslipidemias. A key structural requirement for HMG-CoA reductase inhibitors is the ability to mimic the
normal substrate, product, and/or intermediate transition state associated with this reaction, illustrated in Figure 9-4. Although significant structural variation in the lower rings is tolerated and, in
several cases, enhances activity, the highlighted (boxed) portions of pravastatin and fluvastatin
cannot be altered and are present in all HMG-CoA reductase inhibitors. A change in the stereochemistry of either hydroxyl group or the replacement of either hydroxyl groups with another functional
group alters the ability to correctly mimic HMG-CoA and greatly decreases or eliminates activity. An
ionized carboxylic acid is also required to mimic HMG-CoA. HMG-CoA reductase inhibitors that contain a lactone ring, such as simvastatin, are prodrugs that must first be hydrolyzed to their respective
3,5-dihydroxyacid forms. Finally, the 3-methyl group present within HMG-CoA is not required for
inhibitory activity, as evidenced by the lack of this functional group within any of the inhibitors.
316 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 9-4.The conversion of HMG-CoA to mevalonic acid and inhibitors of HMG-CoA
reductase.
Structure Activity Relationships and Binding Interactions
Drug binding interactions are critical to the mechanism of drug action and in some instances can
bestow selectivity for a specific biological target. Many of the examples discussed below are similar to those listed in the previous section; however, an added emphasis is placed here on binding
interactions that lead to target selectivity, alterations that can convert an agonist to an antagonist,
the role of conformational restriction, and the challenges associated with alteration of essential
functional groups.
Epinephrine and adrenergic agonists (Figure 9-5) have been discussed in Chapters 2 and 7
and provide a good example of how structural changes can affect binding interactions and target
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FIGURE 9-5.Epinephrine and selective a-adrenergic agonists.
selectivity. Epinephrine is an endogenous neurotransmitter that binds to both α and β receptors.
As discussed in Chapter 7, the R configuration of the β-hydroxyl group provides an additional binding interaction compared with the S configuration. As a result, adrenergic agonists that have the
same stereochemistry seen with R-epinephrine are more active than their respective enantiomers.
Replacement of the N-methyl group of epinephrine with an isopropyl group produces isoproterenol, a drug that is essentially devoid of α-adrenergic receptor activity yet has enhanced agonist
activity at the adrenergic β1 and β2 receptors. The reason for this selectivity lies in the fact that the
β receptors contain a larger hydrophobic binding pocket than the α receptors. Thus, from an SAR
perspective, the addition of a larger hydrophobic functional group on the secondary amine provides
β receptor selectivity.
Isoproterenol is classified as a nonselective β agonist. The separation of β1 and β2 receptor activity can be accomplished either by replacing the isopropyl group with a t-butyl group or altering the
positions of the hydroxyl groups on the aromatic ring. The reason for this is that the β1 receptor
requires a catechol ring for agonist activity while structural variation of this ring is allowed for the
β
receptor. Additionally, the β2 receptor can accommodate a bulkier N-substituent (e.g., t-butyl
2
group) whereas this structural change decreases the interaction with the β1 receptor. The use of one
or both of these structural changes provides selective β2 receptor activity, as seen with metaproterenol and terbutaline. Both drugs are used to treat asthma and chronic obstructive pulmonary
disease (COPD) as a result of their selective β2 receptor agonist activity.
While agonist activity at the β2 receptor is useful in treating asthma and COPD, the ability to
block or antagonize the adrenergic β1 receptor is beneficial in the treatment of hypertension and
other cardiovascular disorders. From an SAR point of view, selective β1 receptor activity was accomplished by retaining the highlighted (boxed) portion of isoproterenol (Figure 9-6) and replacing the
catechol ring with a para substituted phenyl ring. A key SAR that is responsible for the β1 selectivity
is the presence of functional groups on the para substitution that are capable of forming hydrogen
bonds with the β1 receptor. The amide group in atenolol provides this structural requirement.
Conformational restriction has been shown to be a key SAR for several classes of drugs. As
previously discussed in both Chapters 2 and 7, the presence of ortho substituents on the lower ring
of diclofenac causes conformational restriction and prevents rotation of this lower ring. This restriction forces the lower ring to align itself perpendicularly to the top ring and therefore is able to bind
318 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 9-6.Structural similarities and differences between isoproterenol (a nonselective
β-adrenergic agonist) and atenolol (a selective a1-adrenergic antagonist).
better to cyclooxygenase enzymes. Other nonsteroidal anti-inflammatory drugs (NSAIDs), such as
mefenamic acid, also have this structural feature.
A similar SAR exists for the 1,4-dihydropyridine (1,4-DHP) class of calcium channel blockers.
These drugs bind to the L-type of potential dependent (or voltage-gated) calcium channels and
block calcium transport into the cell. This action is useful in the treatment of hypertension, ischemic
heart disease, and other cardiovascular disorders. For these drugs to interact with their biological
target, the phenyl ring must be oriented perpendicular to the 1,4-DHP ring. To “lock in” this perpendicular conformation, all 1,4-DHPs have an ortho and/or meta substituent located on the phenyl
ring. This functional group is generally a methyl group, a nitro group, or a chlorine atom. In all cases,
its primary purpose is to provide adequate steric hindrance that restricts rotation and ensures that
the required conformation is present. This is illustrated in Figure 9-7 with nifedipine. The ortho nitro
group provides steric hindrance and ensures a perpendicular orientation of the two rings.
FIGURE 9-7.The structure and a molecular model of nifedipine.
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Although the SAR associated with the 1,4-DHPs appears to be the same as that for the NSAIDs,
there is a subtle difference. In the case of NSAIDs, adding steric hindrance to lock in a perpendicular
conformation enhances their interaction with cyclooxygenase; however, this structural feature is
not an absolute requirement for activity. Many NSAIDs lack this conformational restriction and
retain anti-inflammatory and antipyretic action. In the case of the 1,4-DHPs, it is essential that the
drug molecule contain an ortho or meta substituent. The lack of this structural requirement greatly
decreases or eliminates activity. An important takeaway message is that some SARs define structural
features that are not required yet enhance activity or provide a beneficial effect, while others define
structural features that are absolutely required for pharmacological and therapeutic activity.
It should be noted that there are some instances in which conformational flexibility may be
of greater value than conformational restriction. An example of this was previously discussed in
Chapter 7 with tamsulosin and prazosin. These drugs are α1-adrenergic receptor antagonists and are
approved to treat benign prostatic hyperplasia (BPH) and hypertension, respectively. The increased
conformational flexibility present in tamsulosin allows it to be much more selective for the α
1a
receptor subtype found in the prostate gland compared with prazosin. This selectivity decreases
the side effects observed with prazosin. The explanation or the “why” component of this SAR lies in
the increased conformational flexibility that allows tamsulosin to adopt a preferred conformation
consistent with that required for binding to the α1a subtype. Additionally, the amount of energy
required for tamsulosin to adopt conformations that would allow it to bind to other α1 subtypes
is extremely high. In contrast, prazosin is conformationally rigid, does not need to expend a large
amount of energy to adopt multiple conformations, and can easily bind to multiple subtypes of the
α1 receptor. This lack of selectivity allows prazosin to interact with α1b and α1d receptor subtypes that
are involved in vascular smooth muscle contraction. Although these actions have some benefit in
treating hypertension, they can result in unwanted hypotension in patients treated for BPH.
Angiotensin-converting enzyme (ACE) inhibitors provide a final example of SAR and drug binding interactions. These agents prevent the conversion of angiotensin I, an inactive decapeptide
precursor, to angiotensin II, an octapeptide that is a potent vasoconstrictor at the angiotensin II
receptor, and are useful in the treatment of hypertension, heart failure, and other cardiovascular disorders. This enzyme is a relatively nonspecific zinc protease that catalyzes the cleavage of a dipeptide from the carboxy terminus of a protein or a peptide. Inhibitors of ACE are either dipeptide or
tripeptide analogs that can interact with the enzyme but are not hydrolyzed by the enzyme. A key
SAR for this class of drugs is that the molecule must contain a functional group that can interact
with the zinc atom in the active site of the enzyme. This relationship was briefly discussed in Chapter
6; however, let us examine this SAR in a little more detail. Captopril is a dipeptide mimic that contains a proline residue and a cysteine analog. As shown in Figure 9-8, the sulfhydryl group of captopril can interact with the zinc atom. In the development of captopril, the affinity of this sulfhydryl
group for the zinc atom was found to be more than 1000-fold greater than an analogous carboxylic acid. Unfortunately, the sulfhydryl group caused several problems for some patients, including
rashes and taste disturbances. Additionally, because the sulfhydryl group is able to form inactive
dimers, the drug has a short duration of action and requires multiple daily dosing. Because interaction with the zinc atom is a key SAR, a major challenge in the development of other ACE inhibitors
involved replacement of the sulfhydryl group while retaining an affinity similar to that found with
320 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 9-8.A comparison of captopril with enalaprilat.
captopril. This was accomplished by three major structural changes, as illustrated with enalaprilat
(Figure 9-8). First, the dipeptide analog was replaced by a tripeptide analog. The methyl group of
alanine is similar to that seen with the cysteine analog of captopril while the phenylalanine analog
provided additional binding interactions not present on captopril. Second, the highlighted tetrahedral carbon is better able to mimic the transition state associated with enzyme hydrolysis than a
dipeptide analog. Third, the sulfhydryl group was replaced with a carboxylic acid. The sum of all of
these structural changes produced inhibitors of ACE that were as potent or more potent than captopril yet did not contain a sulfhydryl group.
The above examples illustrate several key points. First, some SARs are essential for activity
and must be met in one way or another. In the case of ACE inhibitors, one such SAR is the ability to
interact with the zinc atom located within the active site of the enzyme. In the case of 1,4-DHPs, the
key SAR is the requirement for the two rings to be oriented perpendicular to one another. Second,
activity can be retained if a key functional group must be replaced due to an adverse effect, a drug
interaction, or another reason. This is seen with captopril and enalaprilat. The loss of potency due
to the loss of the sulfhydryl—zinc interaction seen in captopril was balanced by the other structural
alterations found in enalaprilat. Finally, the binding of a drug molecule to its biological target is often
the result of numerous SARs and not just a single interaction. As seen with all of these examples, the
interactions of key functional groups, the ability to mimic a natural substrate, the presence or absence
or steric hindrance, and the size and orientation of specific functional groups can play a key role in SARs
and the pharmacological and therapeutic action of a drug molecule.
Structure Activity Relationships and Absorption, Distribution,
Metabolism, and Excretion
The absorption, distribution, metabolism, and excretion (ADME) of a drug molecule depends on its
structure and functional groups. As discussed in Chapters 2 and 5, individual functional groups can
enhance the overall water or lipid solubility of a drug molecule. This in turn affects the overall absorption of the drug molecule from its site of administration, its ability or tendency to bind to plasma
proteins, its ability to cross the blood brain barrier, the extent to which it is metabolized, and its duration of action. Additionally, the metabolic pathways discussed in Chapter 8 were all predicated on the
presence of specific functional groups and their location within the structure of the drug molecule. The
following examples illustrate how specific structural features can affect the ADME of a drug molecule.
Certain β-lactam antibiotics cannot be administered orally because the acidic environment of
the stomach causes an intramolecular reaction that destroys the β-lactam ring. The mechanism of
this acid catalyzed degradation was discussed in Chapter 2. Also discussed in Chapter 2 was the fact
that this degradation could be significantly decreased if an electron withdrawing group was present
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on the α carbon. This is illustrated below with cefaclor and penicillin V. This SAR applies to both
penicillins and cephalosporins and in part dictates whether the antibiotic is orally active or must be
administered via injection.
A similar SAR is seen with estrogens and androgens. The endogenous compounds estradiol and
testosterone cannot be administered orally because their respective C17 hydroxyl groups are rapidly oxidized, as shown in Figure 9-9. From an SAR perspective, one way to decrease this rapid
FIGURE 9-9.Estradiol, testosterone, and orally active analogs with 17` substituents.
322 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
metabolism is to add a 17α substituent, as shown in methyltestosterone and ethinyl estradiol. This
functional group blocks the oxidation of the C17 hydroxyl group and allows these drugs to be administered orally.
Within the tetracycline class of antibiotics, a key SAR is the presence or absence of a C6 hydroxyl
group as this functional group affects both oral absorption and the duration of action. Similar to
the β-lactam antibiotics, the presence of this functional group leads to an acid-catalyzed dehydration and rearrangement in the stomach, resulting in inactivation of the tetracycline (Figure 9-10A).
Although this does not prevent the oral use of tetracycline, it does decrease the overall oral absorption of the drug. Analogs that lack a C6 hydroxyl group (e.g., doxycycline) are not subject to this
acid-catalyzed rearrangement and therefore exhibit better oral absorption. The oral absorption of
FIGURE 9-10.A comparison of tetracycline and doxycycline and the role of a C
group in (A) acid stability and (B) water solubility.
hydroxyl
6
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tetracycline is approximately 58% while the oral absorption of doxycycline is approximately 93%.
As discussed in Chapter 2, a C6 hydroxyl group also significantly enhances the water solubility of a
tetracycline due to its ability to form hydrogen bonds with water. When the hydroxyl group is moved
to the adjacent C5 atom, internal hydrogen bonding with the tertiary amine decreases the ability to
form hydrogen bonds with water. This difference in the binding interactions with water results in
significant differences in partition coefficients, with the partition coefficient of doxycycline (0.95)
being more than 15 times greater than that of tetracycline (0.056). This is illus trated in Figure 9-10B.
Because doxycycline lacks a C6 hydroxyl group, it is more lipophilic and is bound to plasma proteins
to a much greater extent than tetracycline. As discussed in Chapter 5, the ability of a drug molecule
to bind to plasma proteins decreases its availability to be eliminated and can increase its duration
of action. In comparing tetracycline and doxycycline, it is found that their respective half-lives are
10 hours and 15 hours.
In Chapter 5, we discussed the advantages of enhancing water and lipid solubility through the
use of salts and ester prodrugs and the addition or alteration of functional groups. Many of the
examples discussed in that chapter can be viewed as SARs that can be applied to other drug molecules. A sample listing of these is provided in Table 9-1. Additional details associated with these
examples can be found in Chapter 5.
As a final example, let us examine a key structural difference between sedating and nonsedating antihistamines. Sedating antihistamines such as diphenhydramine and cyclizine are much more
lipophilic than nonsedating antihistamines such as fexofenadine and cetirizine (Figure 9-11). In
comparing the drug structures, it should be noted that all four molecules contain aromatic rings, aliphatic chains or rings, and at least one tertiary amine. The primary structural difference is that both
fexofenadine and cetirizine contain an ionizable carboxylic acid that enhances the overall water solubility of these two drugs. Fexofenadine also has two hydroxyl groups that can form hydrogen bonds
with water. The ability to cause sedation relies on the ability of the drug to cross the blood brain
barrier and reach specific receptors within the central nervous system (CNS). Diphenhydramine and
cyclizine have sufficient lipid solubility to enter the CNS and cause sedation whereas fexofenadine
and cetirizine are more water soluble and lack this ability. In terms of SAR, the ability of an antihistamine to produce sedation depends on its lipid solubility, which is determined by the functional
groups present within its structure.
Structure Activity Relationships and Drug
Interactions and Adverse Drug Reactions
There are several mechanisms by which drug molecules can produce adverse effects and drug interactions with other coadministered drugs. A partial list includes those that are due to normal extensions of a desired pharmacological action (e.g., diuretics can cause excess urination); those that are
due to a lack of selectivity and the resulting interaction with an unwanted enzyme, receptor, or other
biological target; and those that are due to alterations of CYP metabolic enzyme function (discussed
in Chapter 8). Additionally, some drug interactions and adverse drug reactions can be related directly
to specific functional groups present on a drug molecule or specific chemical properties of a drug
molecule. The following examples illustrate how SARs can impact drug interactions and adverse
drug reactions.
Some adverse drug reactions have been linked to specific functional groups present within drug
molecules. As previously mentioned in this chapter, the sulfhydryl functional group present in captopril (Figure 9-8) was responsible for abnormal taste disturbances and rashes. Due to these adverse
effects, all subsequently developed ACE inhibitors lack this functional group. An additional example
of this concept can be seen with the methyl-tetrazole-thiomethyl (MTT) group present within the
structure of cefotetan (shown below). This particular functional group, when present in cephalosporin antibiotics, has been shown to be responsible for acute alcohol intolerance as well as serious
bleeding due to platelet dysfunction and/or thrombocytopenia. This particular functional group was
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