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474 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Levonorgestrel (Level 3)
1. Answers provided below.
Name of Functional
Group
A Ketone Hydrophobic (R) Absorption (R)
B Alkene Hydrophobic Absorption
C Cycloalkane Hydrophobic Absorption
D Alkyne Hydrophobic Absorption
E Tertiary alcohol Hydrophobic (R) Absorption (R)
R = carbon scaffolding.
Character: Hydrophobic,
Hydrophilic, or both
Hydrophilic (C=O) Solubility (C=O)
Hydrophilic (OH) Solubility (OH)
Function: Contribute to Aqueous
Solubility or Absorption
2. Both the ketone and tertiary alcohol contain electronegative oxygen atoms, which inductively attract/withdraw electron density from the carbon atoms attached to them. This
means that both the tertiary alcohol and ketone are electron withdrawing groups based on
an inductive effect.
The tertiary alcohol is attached to aliphatic carbon atoms and therefore cannot participate
in any resonance effects. The ketone is part of an α, β unsaturated ketone and there is a
limited amount of resonance contribution as an electron withdrawing group.
3. Levonorgestrel has several functional groups that are exclusively hydrophobic in character.
This should promote absorption (lipid solubility) across the skin if the drug is formulated as
a patch. Distribution into the plasma is facilitated by both the ketone and tertiary alcohol,
which are both hydrophilic in character and able to participate in H-bonding with water
due to the electronegativity differences between the C and O atoms or O and H atoms,
respectively. This hydrophilic character contributes to aqueous solubility in the blood.
Because levonorgestrel has functional groups that contribute to both the hydrophobic and
hydrophilic character (as just described) of the drug, it is possible for it to be administered
orally. Dissolution and solubility in the aqueous contents of the stomach, as well as distribution into the plasma, are facilitated by functional groups that contribute to the hydrophilic character of the drug. Absorption across the lipophilic GI membranes and then across
target cell membranes is facilitated by functional groups that contribute to the hydrophobic character of the drug.
4. In Chapter 3, we described a nonelectrolyte as a drug that does not dissociate into ions in
solution (contains only neutral functional groups) and an electrolyte as a drug that does
dissociate into ions in solution (contains one or more acidic or basic functional groups or
a quaternary amine). Levonorgestrel is a nonelectrolyte. It does not contain any ionizable
(acidic or basic) functional groups and is comprised only of neutral functional groups.
5. In Chapter 3, we discovered that human serum albumin (albumin) binds to a variety of
endogenous substances and drugs. It is fairly nonspecific in its binding requirements
although it prefers to interact with acidic molecules more so than basic molecules and
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 475
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prefers to interact with drugs that are hydrophobic in character more so than those that are
hydrophilic in character. Levonorgestrel has no acidic or basic functional groups but is comprised of functional groups that contribute a significant amount of hydrophobic character.
Because of this hydrophobic character, levonorgestrel is suitable for binding to albumin.
6. In Chapter 5, we learned that log P represents a ratio of the solubility of the unionized drug
in an organic solvent to the solubility of the same unionized drug in an aqueous environment. The structural evaluation of levonorgestrel reveals that this drug is unable to be ionized, so we are really looking at the ratio of the solubility of the drug in an organic solvent
to the solubility of the same drug in an aqueous environment.
Part A: If we want the log P value to decrease, we need to increase the amount of drug
that is soluble in an aqueous environment (larger denominator in the ratio). This means
that our structural modification should add hydrophilic character to the drug molecule. In
Chapter 5, we learned that a water-soluble prodrug could be created (e.g., create a sodium
phosphate ester or a sodium succinate ester). The prodrug would be metabolically cleaved
to reveal the parent drug. Another solution is to modify the drug structure by adding one
or more hydrophilic functional groups (e.g., alcohol, amine). A word of caution with this
last recommendation: Functional group addition must not interfere with the critical binding
interactions between a drug and its biological target.
Part B: If we modify the molecule to increase the hydrophilic character of the molecule,
then we have also increased the water solubility of the molecule.
Part C: Norgestimate has a log P = 4.11, which is larger than levonorgestrel. The numerator
represents the solubility of the drug in an organic solvent. So, from a structural evaluation
perspective, why is norgestimate more lipid soluble than levonorgestrel? As you can see,
the tertiary alcohol has been converted into a lipid-soluble ester prodrug. This modification
enhances the lipid solubility of the drug and contributes to the increase in log P value. In
addition, the ketone has been converted into an oxime, which can be metabolically converted into the parent ketone. The oxime is actually more water soluble than the parent
ketone, so this modification is not what is enhancing the lipid solubility and causing an
increase in the log P value.
7. Both ethinyl estradiol and levonorgestrel contain a hydrophobic steroid scaffold (infrastructure) on which several substituents are positioned. The hydrophobic steroid skeleton
resides in the hydrophobic cavity found as part of both the estrogen and progesterone
receptors. Additional structural evaluation reveals that levonorgestrel contains a ketone
(H-bond acceptor) and a tertiary alcohol (H-bond acceptor and donor) on opposite ends
of the steroid skeleton. Ethinyl estradiol has a phenol (H-bond acceptor and donor) and a
tertiary alcohol (H-bond acceptor and donor) on opposite ends of that steroid skeleton.
Given that the estrogen receptor requires that receptor agonists interact with both the
hydrophobic cavity as well as via two critical H-bonding interactions, it is no surprise that
levonorgestrel has some agonist activity at the estrogen receptor.
8.
Part A: As you learned in Chapter 7, the trans designation refers to substituents being
located on opposite sides of a double bond or ring system in geometric isomers.
476 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Part B: In levonorgestrel there are several places where the trans designation is relevant.
Each of the following shows a unique trans relationship within levonorgestrel.
Parts C and D: When functional groups are cis to one another, they are found on the same
side of a double bond or ring system. In the case of the levonorgestrel analog that has
a mixture of cis/trans relationships, there are several cis relationships, two of which are
boxed. Only one of these, box #1, has an effect on the overall shape of the steroid skeleton.
As you can see from the picture below, the steroid is no longer flat as a result of the cis ring
junction found in box #1. This would make interaction with the progesterone receptor’s
hydrophobic cavity less than optimal. Not only is the steroid skeleton a different shape but
also the ketone is now located in a different place in space and is unlikely able to interact
via H-bonding with the estrogen receptor. For both types of receptors, this cis configuration
places a hydrophilic functional group (ketone) in the space that should be occupied only
with hydrophobic functional groups. (Note: The structural activity relationships [SARs] for
the progesterone receptor require the presence of the double bond in the A ring, so this
analog does not bind to and activate the progesterone receptor.)
9. Part A: As we learned in Chapter 8, a drug that is subject to first-pass metabolism is
metabolized by the liver prior to reaching systemic circulation. This decreases the amount
of drug that is bioavailable. Drugs that are lipid soluble are typically subject to first-pass
metabolism.
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Part B: As we identified earlier in this evaluation, levonorgestrel contains a significant
amount of hydrophobic character. You might have expected that it was sufficiently hydrophobic to undergo first-pass metabolism.
Part C: Possible Phase I transformations: allylic oxidation; epoxidation/peroxidation. Possible
Phase II transformations: glucuronidation; sulfation (minor).
Montelukast and Zafirlukast (Level 2)
1. Shown below are the reported pKa values for the functional groups. As discussed in Chapter
3, pKa ranges can occasionally overlap; therefore, it is possible for a carboxylic acid to have
a pKa value of 3.1 and an aromatic heterocyclic amine to have a pKa value of 4.4. Please note
that even if these pKa values were switched, the answers to the ionization questions would
remain the same.
Functional
Group
Carboxylic
Acid
Aromatic
heterocyclic
amine
Sulfonamide Acidic Unionized Ionized Ionized Ionized Ionized
Acidic or
Basic
Acidic Unionized Ionized Ionized Ionized Ionized
Basic Ionized Unionized Unionized Unionized Unionized
1.9 5.4 6.1 7.2 8.3
Primarily Ionized or Unionized
2. To use the Rule of Nines, the difference between the pH and the pKa must be an integer (i.e., 1, 2, 3). In evaluating the above 15 scenarios, there are three scenarios that meet
this criterion: the carboxylic acid of montelukast (pK
= 4.4) at a urine pH of 5.4, the
a
aromatic heterocyclic amine of montelukast (pKa = 3.1) at a cellular pH of 6.1, and the
sulfonamide of zafirlukast (pKa = 4.3) at a solution pH of 8.3. For the carboxylic acid of
montelukast, |pH – pKa| is equal to 1; thus, there is a 90:10 ratio. Because the carboxylic
acid (pKa = 4.4) would be primarily ionized in a basic environment (pH = 5.4), we can use
this ratio to determine that it would be 90% ionized. For the aromatic heterocyclic amine
of montelukast, |pH – pKa| is equal to 3; thus, there is a 99.9:0.1 ratio. Because the aromatic
heterocyclic amine (pKa = 3.1) is a basic functional group, it would be primarily unionized
478 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
in a basic environment (pH = 6.1). We can use this information to predict that it would be
0.1% ionized. For the sulfonamide of zafirlukast, |pH – pKa| is equal to 4; thus, there is a
99.99:0.01 ratio. Because the sulfonamide (pKa = 4.3) is an acidic functional group, it would
be primarily ionized in a basic environment (pH = 8.3). Thus, we can use this information to
predict that it would be 99.99% ionized.
3. The presence or absence of specific functional groups can affect the acidity or basicity of
ionizable functional groups. In the case of zafirlukast, the adjacent carbonyl group allows
for increased resonance stabilization of a negative charge. As shown below, once the
acidic proton dissociates, the resulting negative charge can be equally distributed among
the nitrogen atom and the three oxygen atoms. This enhanced resonance stabilization
increases the acidity of the sulfonamide, resulting in a lower pKa value.
4. A sodium salt is an inorganic salt of the parent drug. The primary purpose of using an inorganic salt is to enhance the water solubility of a drug molecule. This in turn enhances its
solvation and dissolution with the aqueous environment of the gastrointestinal (GI) tract.
Because montelukast must be administered as an inorganic salt and zafirlukast does not
have this requirement, this indicates that zafirlukast has higher water solubility than montelukast. In evaluating their structures, it is found that montelukast and zafirlukast each
contain three water soluble functional groups; the remainder of their structures is comprised of alkyl chains, aromatic rings, a thioether, and a halogen. These latter functional
groups bestow lipid solubility to their respective drug molecules. A key difference between
these two structures is the overall nature of their water-soluble functional groups. The
sulfonamide of zafirlukast has a wider charge distribution (four atoms) than does the
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 479
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carboxylic acid of montelukast (two atoms; Comparison A). Additionally, the carbamate
group of zafirlukast has the ability to form more hydrogen bonds with water than does
the tertiary hydroxyl group of montelukast (Comparison B). The ability to act as hydrogen bond acceptors would be expected to be similar for the methoxy group of zafirlukast
and the aromatic heterocyclic amine of montelukast (Comparison C). Please note that the
nitrogen atom of the indole ring within the structure of zafirlukast is an extremely weak
base (pKa < 0.1) and cannot participate in hydrogen bonds. This is because the lone pair of
electrons on the nitrogen atom are required for the aromaticity of the indole ring.
In addition, the overall lipid-soluble character of montelukast is greater than that of zafirlu-
kast. The structure of montelukast contains 34 aromatic or aliphatic carbon atoms (as well
as a halogen atom) whereas the structure of zafirlukast contains only 28. The combination
of a lower water-soluble nature and a higher lipid-soluble nature is responsible for the need
to utilize a sodium salt for the oral administration of montelukast.
5. Let us evaluate these two drug molecules separately. The structure of montelukast contains a carboxylic acid that could participate in an ionic bond with the leukotriene receptors. It also contains two functional groups, the tertiary hydroxyl group and the aromatic
heterocyclic amine, that could participate in a hydrogen bonding interaction as an acceptor.
As shown below, the structure of montelukast contains four separate regions that could
interact with the three hydrophobic pockets of the receptor via van der Waals and hydrophobic interactions.
480 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Similarly, the structure of zafirlukast contains a sulfonamide group that could participate in
an ionic bond with the leukotriene receptor as well as two functional groups, the methoxy
group and the carbamate, that could participate in a hydrogen bonding interaction as an
acceptor. As shown below, the structure of zafirlukast also contains four separate regions
that could interact with the three hydrophobic pockets within the receptor.
6. The structure of montelukast contains one chiral center, one nonaromatic double bond,
and numerous rotatable single bonds. Thus, it can have an enantiomer, a geometric iso-
mer, and numerous conformational isomers. It cannot have diastereomers. Examples are
shown below.
The structure of zafirlukast does not contain a chiral center or a nonaromatic double bond;
therefore, it cannot have an enantiomer, diastereomers, or geometric isomers. Due to the
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 481
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presence of a number of freely rotatable single bonds, zafirlukast can have conformational
isomers. One example is shown below.
7. Plasma proteins are used by the human body to transport endogenous molecules in the
plasma from one cell to another. Given that the plasma is water soluble, these proteins are
primarily required to carry those endogenous molecules that have a high level of lipid solubility (e.g., estradiol, cholesterol, hydrocortisone). This is also true for exogenously administered drug molecules. Drug molecules that have a more lipid-soluble character have a
greater affinity for plasma proteins than do those that have a more water-soluble character. Thus, using the calculated log P values provided for montelukast and zafirlukast, it
would be expected that these two drug molecules would be highly plasma protein bound.
The primary purpose of drug metabolism is to enhance the removal of the drug molecule
from the human body. Drug molecules that already possess adequate water solubility, and
thus can be readily eliminated, generally undergo minimal or no metabolism whereas drug
molecules that are highly lipid soluble often undergo extensive metabolic transformation.
Thus, using the calculated log P values provided for montelukast and zafirlukast, it would be
expected that these two drug molecules would undergo extensive hepatic meta bolism.
8. The metabolic transformations are listed below.
y Metabolite A: Phase II; Glucuronic acid conjugation
y Metabolite B: Phase I; S-oxidation
y Metabolite C: Phase I; ω-oxidation
y Metabolite D: Phase I; Benzylic oxidation
9. Pathway A (Methylation): No. Methylation is a Phase II metabolic transformation that
requires a catechol, a phenol, an amine, or a sulfhydryl functional group. Because none
of these functional groups are present within the structure of zafirlukast, this metabolic
transformation cannot occur.
Pathway B (Aromatic Oxidation): Phase I; Yes
482 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Pathway C (Hydrolysis): Phase I; Yes
Pathway D (Oxidative O-Dealkylation): Phase I; Yes
Pathway E (Benzylic Oxidation): Phase I; Yes
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Nadolol and Other a-Adrenergic Antagonists (Level 3)
1. Functional group names and hydrophilic or hydrophobic character provided below.
Functional Group Name Hydrophilic or Hydrophobic
A Secondary hydroxyl (secondary
alcohol)
B Ether oxygen Hydrophilic due to its ability to form hydrogen
C Alkyl group; alkyl chain; aliphatic
chain
D Secondary amine Hydrophilic due to its ability to ionize and form
E Alkyl group; t-butyl group Hydrophobic due to its inability to ionize or
F Aromatic ring; phenyl ring Hydrophobic due to its inability to ionize or
Hydrophilic due to its ability to form hydrogen
bonds with water as either a donor or an
acceptor
bonds with water as an acceptor
Hydrophobic due to its inability to ionize or
form hydrogen bonds with water; hydrocarbon
functional groups enhance lipid solubility
ion–dipole interactions with water
form hydrogen bonds with water; hydrocarbon
functional groups enhance lipid solubility
form hydrogen bonds with water; hydrocarbon
functional groups enhance lipid solubility
2. Epinephrine is a naturally occurring hormone that acts as an agonist on both α- and
β-adrenergic receptors. The secondary amine, the secondary hydroxyl group, and the
phenolic hydroxyl groups present within the structure of epinephrine provide key binding interactions with both the α- and β-adrenergic receptors. As discussed in Chapter 9,
replacement of the N-methyl group of epinephrine with a larger alkyl group, such as the
t-butyl group on nadolol, provides selectivity for β-adrenergic receptors due to a steric
effect. The secondary amine, methylene, and secondary hydroxyl group of nadolol provides
an atom for atom mimic of epinephrine. The major difference in these two structures lies in
the spacing between the basic nitrogen atom and the aromatic ring systems as well as the
positioning/orientation of the phenolic or alicyclic hydroxyl groups. The orientation seen
in epinephrine produces an agonist effect when it binds to the β-adrenergic receptor while
the larger bicyclic ring system produces an antagonist effect.
3. Epinephrine is a naturally occurring endogenous agonist at the β-adrenergic receptors. The
structure of epinephrine contains one chiral center with an R configuration that maximizes
the binding interactions of the secondary hydroxyl group with the adrenergic receptors.
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