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234 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Benefits of Conformational Restriction
Restriction of conformational flexibility is a commonly used drug development strategy to “lock” a
drug molecule into a desired conformation. To illustrate the potential benefits that could possibly
be gained by this strategy, let us consider the following hypothetical example.
Assume a drug molecule contains two functional groups, X and Y, which are located on adjacent carbon atoms and are essential for pharmacological activity. Further assume that the drug is
capable of binding to three different receptor types or subtypes. Given this scenario, it would be
beneficial to determine if the drug is binding to the three receptors in similar or distinct conformations. Conformational restriction could help to provide this information. Additionally, there are
many conformations of X and Y relative to one another. Of these, let us consider the four conformations (A–D) shown in Figure 7-18.
FIGURE 7-18.Conformations of a hypothetical drug molecule (the eclipsed views of
conformations B and D have been slightly offset to view the atoms).
As an idealized case, let us assume that previous research has determined that the drug acts
on its three receptors in three different conformations to produce two beneficial effects (antihypertensive and hypoglycemic effects) and one very prevalent side effect (dry mouth). We also assume
that the following information is true: when the molecule is in conformation A, it binds to receptor 1
and produces an antihypertensive effect; when the molecule is in conformation B, it binds to receptor 2 and produces a hypoglycemic effect; and when the molecule is in conformation C, it binds to
receptor 3 and produces the side effect. Because the active conformations are known, it should be
possible to use conformational restriction to develop specific agonists and/or antagonists for these
receptors. By locking the molecule in either conformation A or B, it should be possible to elicit only
the desired beneficial effect without the side effect or any other unnecessary effects. Carrying this
idealistic example one step further, assume that the drug has a high affinity for hepatic metabolic
enzymes when it is in conformer D. Conformationally restricted analogs of conformers A or B would
then be expected to have an increased duration of action over the parent compound in addition to
the above-stated advantages.
Although the hypothetical example is an idealized case, it is not that far-fetched. Small, conformationally flexible neurotransmitters such as acetylcholine, norepinephrine, dopamine, and
histamine are known to bind in different conformations to different receptor subtypes to produce
different effects. As an example, acetylcholine binds to its metabolizing enzyme, acetylcholinesterase, in its trans conformation. This information, as well as the structures of naturally occurring
acetylcholinesterase inhibitors, led to the development of pyridostigmine bromide and neostigmine bromide (Figure 7-19). The aromatic rings present in these two drugs provide conformational
restriction and lock the positively charged ammonium group in a trans orientation to the carbamate group, a functional group that is analogous to the acetyl ester found in acetylcholine. Due in
part to this conformational restriction, these drugs can bind to acetylcholinesterase and inhibit this
enzyme. The binding and inhibition indirectly increase the concentration of acetylcholine and can be
used to treat myasthenia gravis.
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FIGURE 7-19.Pyridostigmine bromide and neostigmine bromide: conformationally
restricted carbamate analogs of
Another example of the benefits of conformational restriction can be seen with certain NSAIDs,
a class of drug molecules previously discussed in this chapter. These drug molecules inhibit cyclooxygenase enzymes, resulting in decreased production of inflammatory prostaglandins. As part of their
mechanism of action, these drug molecules must bind to the active site of cyclooxygenase and mimic
arachidonic acid, the natural substrate of the enzyme. The binding of fenoprofen and diclofenac to
cyclooxygenase involves three key interactions, shown in Figure 7-20. The acidic carboxylic acid
forms an ionic bond with a positively charged arginine residue. The adjacent (or “top”) aromatic ring
forms van der Waals interactions with hydrophobic side chains of various amino acids. The second
(or “bottom”) aromatic ring binds in a hydrophobic trough that is under the “top” ring and somewhat perpendicular to the “top” ring. Both fenoprofen and diclofenac are able to bind to the active
site of cyclooxygenase; however, the highlighted ortho chloro groups present on diclofenac confer
steric hindrance that locks the “bottom” ring perpendicular to the “top” ring. As a result, diclofenac
is already locked into the active conformation and does not need to expend as much binding energy
to fit into the active site. This is reflected in the relevant affinities or potencies of these two drugs.
Diclofenac is dosed at 50 to 75 mg two or three times daily (BID or TID) whereas fenoprofen is dosed
at 400 to 600 mg three or four times daily (TID or QID).
trans
acetylcholine.
FIGURE 7-20.A comparison of fenoprofen and diclofenac binding to cyclooxygenase.
236 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
In summary, conformational restriction can potentially result in a number of pharmacological
and therapeutic benefits. Specifically, conformational restriction can increase the specificity of a
drug molecule for a single biological target, it can increase the duration of action of a drug molecule,
and it can decrease adverse effects. As the NSAIDs illustrate above, although a flexible drug can
assume an unfavorable conformation, this requires energy. A conformationally rigid analog with
all the necessary groups in the proper orientation would not require this energy and should have a
higher affinity for the receptor.
It should also be noted that there are some situations in which conformational flexibility, rather
than conformational restriction, bestows a beneficial effect. An example of this can be seen with
tamsulosin and prazosin, two drugs previously discussed that can be used to treat benign prostatic
hyperplasia (Figures 7-15 and 7-16). These drugs relax the bladder neck and the prostate by blocking the α1-adrenergic receptor. This causes less pressure on the urethra and increases urine flow.
Three subtypes of α1 receptors have been identified: α1a, α1b, and α
human prostatic smooth muscle contraction whereas α
and α1d receptors are involved in vascular
1b
The α1a receptors mediate
1d.
smooth muscle contraction. Both α1a and α1b, are present in the prostate, with approximately 70%
being the α1a receptors. As compared with prazosin, tamsulosin is much more selective for the α1a
subtype. This selectivity has been proposed to be due to the increased conformational flexibility of
tamsulosin. As a result, tamsulosin interacts with vascular smooth muscle much less than prazosin
and therefore causes much less orthostatic hypotension.
Summary of Key Points Regarding Conformational Isomers
• Unlike configurational isomers (i.e., enantiomers, diastereomers, and geometric
isomers), conformational isomers are not distinct molecules but rather different
orientations of the same molecule.
• The number and location/position of rotatable bonds determine whether a drug mol-
ecule is conformationally flexible or conformationally rigid.
• The preferred conformation(s) of a drug molecule are established primarily by
electronic and steric effects. Conformations that maximize attractive electronic
interactions and minimize steric repulsive interactions are preferred.
• The active conformation(s) of a drug molecule are established by its biological target.
To bind to its biological target, the drug molecule must be able to assume a conformation that has a complementary orientation of key functional groups.
• The energy required to convert a drug molecule from its preferred conformation to
its active conformation comes from the energy that is released when the drug molecule
binds to its biological target.
• Conformational restriction of a drug molecule can potentially provide several
pharmacological/therapeutic benefits, including enhanced specificity for a given
biological target, decreased metabolism and increased duration of action, and
decreased adverse effects.
• Conformational flexibility can also provide beneficial pharmacological/therapeutic
benefits depending on the specific drug or drug class.
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STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
1. Identify all chiral centers and potentially prochiral centers that are present within the
structure of venetoclax.
2. Is it possible for venetoclax to have the following:
A. Enantiomers?
B. Diastereomers?
C. Geometric isomers?
D. Conformational isomers?
3. If you answered YES to any of the questions in Question 2, draw an appropriate isomer.
4. Nitrogen atoms that have sp3 hybridization can readily undergo inversion of their lone pair
of electrons, as shown below. Due to this inversion, a nitrogen atom can readily convert
the orientations of its lone pair of electrons. Given this piece of information, predict the
preferred conformation of the piperazine ring (ring A) seen in venetoclax.
5. Identify any steric factors that would help to dictate the preferred conformation of the pyrrolopyridine ring (ring B) relative to its surrounding functional groups.
238 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Checkpoint Drug 2: Elamipretide
As a peptide-based drug, elamipretide is derived from naturally occurring and modified amino acids.
In Chapter 2 you identified that there are four amino acids present in this drug molecule. Every
amino acid (with the exception of glycine) has a chiral center.
1. How many chiral centers are present in elamipretide? Circle each chiral carbon.
2. For each of the four amino acid/amino acid derivatives, determine how many potential
prochiral carbons are present.
3. Consider each of the following types of isomers. Describe what would need to change
structurally to produce each type of isomer.
A. Enantiomer
B. Diastereomer
4. Provide an explanation as to why geometric isomers are not possible for elamipretide.
5. Based on your evaluation of elamipretide, is it conformationally flexible or conformationally rigid? Provide a brief rationale for your answer.
REVIEW QUESTIONS
1. Consider each of the structures below and do the following:
A. Determine whether a chiral carbon is present.
B. Place an asterisk next to the chiral carbon(s) that is present.
C. For each of the structures below, determine whether each of the circled atoms is
prochiral or not.
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2. Determine which enantiomer (R/S) is drawn below. List the four unique substituents
attached to the chiral carbon and their priorities based on the CIP system.
3. List three properties that are identical between R and S enantiomers and one property that
may be very different.
4. Match the enantiomer designations with the correct definition(s). Each definition may be
used more than once, and each designation may be matched with more than one definition.
240 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
(+)/(–) 1. Absolute configuration
d/l 2. Steric arrangement of atoms about a chiral carbon
d/l 3. Direction that enantiomer rotates plane polarized light
R/S 4. Dextrorotatory/levorotatory
5. For a molecule that has three chiral centers (R,S,S), answer the following questions:
A. How many (+)/(–) designations are used to describe how the molecule rotates plane
polarized light?
B. Determine which of the following statements is/are true related to this molecule:
1. It can have an enantiomer.
2. It can have a diastereomer.
3. It can have a geometric isomer.
4. It can have conformational isomer.
6. Sotalol is indicated for the management of arrhythmias and is marketed as a racemate.
The S isomer is a potassium channel blocker, and the R isomer is both a potassium channel
blocker and nonselective β antagonist. Provide a brief rationale for why it is possible that
these enantiomers have different pharmacological properties.
7. Fenfluramine was a drug used as an appetite suppressant in the late 1980s and early 1990s
and was sold as a racemate. -Fenfluramine was an effective appetite suppressant; however, -Fenfluramine caused significant drowsiness. To combat the fatigue caused by the L
isomer, this drug was combined with phenteramine, which has both stimulant and moderate weight loss activity. Evaluate the enantiomers of fenfluramine and phentermine, circle
any chiral carbon atoms, and box any prochiral carbon atoms. Provide a brief rationale for
why the enantiomers of fenfluramine have different pharmacological properties.
8. Describe how diastereomers are the same and how they are different from enantiomers.
Circle all chiral centers in both of the isomers of dextromethorphan drawn below. Determine
if the two structures drawn below represent a pair of diastereomers or enantiomers.
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9. Doxepin is administered as an 85 (E):15 (Z) mixture of stereoisomers. The E-stereoisomer
is a norepinephrine reuptake inhibitor. The Z-stereoisomer is a serotonin selective reuptake
inhibitor used in the treatment of depression. Determine the priority of the three double
bond substituents using the CIP system.
10. Shown below are the structures of acebutolol, estradiol, cefamandole, and nifedipine. For
each of these drugs:
A. Identify all chiral centers.
B. Identify if it can have an enantiomer. Provide an explanation for your response.
C. Identify if it can have a diastereomer. Provide an explanation for your response.
D. Identify if it can have a geometric isomer. Provide an explanation for your response.
242 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
11. Shown below are the structures of fluvastatin and its enantiomer. Which of the following
properties/actions would be expected to be identical for fluvastatin and its enantiomer and
which would be expected to be different?
A. Hepatic metabolism
B. Water solubility
C. Adverse effect profile
D. Active renal reabsorption by transport proteins
E. Potency (dosage given)
F. Percent ionization at a pH of 7.4
12. Shown below is the structure of pioglitazone with three single bonds highlighted (A-C). For
each of these highlighted bonds, draw a conformational isomer that could result due to a
rotation about the bond and indicate how your conformational isomer could change the
binding of pioglitazone to its target receptor.
8
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DRUG METABOLISM
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Discuss the key concepts governing drug metabolism.
• Explain the general mechanistic requirements for cytochrome P450 oxidation as well as
identify the factors that can alter the effects of these enzymes.
• Identify the metabolic transformations that are required to convert a given drug molecule
to a given metabolite.
• Predict the possible metabolic transformations that could occur for a given drug molecule.
• For any given functional group within a drug molecule, identify the possible types of
metabolic transformations it could undergo.
• For each Phase I metabolic transformation, draw key intermediates and/or the final
metabolic product.
• For each Phase II metabolic transformation, draw and/or identify the activated
intermediate, identify the transferring enzyme, identify the functional groups that can
be conjugated by this path, and identify any deconjugating enzymes.
The primary purpose of drug metabolism is to enhance the removal of drug molecules from
the body by altering or adding functional groups. Drug metabolism is also important for activating
prodrugs, converting less active drugs to more active metabolites, inactivating drug action, deactivating toxic compounds, and, in some cases, producing toxic metabolites.
Metabolic transformations can be divided into two main categories: Phase I metabolism and Phase
II metabolism.
y Phase I metabolic transformations alter functional groups that are initially present within a
drug molecule or a biomolecule. There are three types of Phase I transformations: oxidation, reduction, and hydrolysis. Oxidation is the most prevalent of these three. In general,
these transformations increase the water solubility of the drug molecule; however, this
increase is not always sufficient enough to allow the drug to be readily excreted.
DOI 10.37573/9781585286959.008
243
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