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364 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
9. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations that would be required to form each of the metabolites. For each metabolic
transformation, indicate if it is a Phase I transformation or a Phase II transformation.
CEFPROZIL (LEVEL 1)
Cefprozil is a second-generation cephalosporin that exhibits good gram (+) activity with improved
gram (–) activity as compared with the first generation cephalosporins. Effective against most bacteria that cause upper and lower respiratory infections as well as skin infections, cefprozil was a
first-line anti-infective agent until an increase in the incidence of resistance and the development of
newer agents decreased its “favored” status.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 365
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1. Conduct a complete structural evaluation of cefprozil and use the information in the grid to
inform your answers to the questions that follow:
Function:
Name of
Functional
Group
a
“None” is a possible answer.
Character:
Hydrophilic and/
or Hydrophobic
Character:
Acidic, Basic,
or Neutral
(Provide
When
pK
a
Relevant)
Function:
↑ Solubility
and/or ↑
Absorption
Function:
Interaction(s)
Possible with
Biological
Target at
Physiologic
pH (7.4)
Amino Acids
That Can
Interact with
Functional
Group via
H-bonding
(at pH = 7.4)
a
2. Based on the information in the structure evaluation grid, determine if cefprozil is an acidic,
basic, or amphoteric drug. Provide a brief explanation for your answer.
3. Cefprozil is administered orally as a tablet or liquid suspension. Consider each of the acidic
and basic functional groups and determine whether each group will be predominantly
ionized or unionized as it moves through the gastrointestinal (GI) tract, into systemic
circulation, and then into the urine. (The relevant pKa values = 10, 1.7, and 7.2.) Complete
the grid below.
Answer
Name of
Functional
Group
Acidic or
Basic (pK
Ionized or
Unionized
at pH = 5
)
(Saliva)
a
Ionized or
Unionized
at pH = 1
(Stomach)
Ionized or
Unionized
at pH = 7.4
(Plasma)
Ionized or
Unionized
at pH = 8
(Intestine)
Ionized or
Unionized
at pH = 6
(Urine)
4. Given the predominant ionization state of these acidic and basic functional groups as they
traverse the GI tract and the information in the structure evaluation grid, determine in
which GI compartment(s) drug absorption could occur.
5. There are two geometric isomeric forms of cefprozil, both of which are active as antibacterial agents. Draw the two geometric isomers and identify which is the Z isomer and which
is the E isomer. Would you expect these two isomers to have the same or different physical
and chemical properties?
366 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
6. Circle all of the chiral carbons found within cefprozil. Determine whether diasteromeric
forms of ceprozil are possible. If diastereomers are present, then determine if they would
be expected to have similar or different physical and chemical properties.
7. Approximately 60% of a cefprozil dose is recovered in the urine unchanged. Because impairment in hepatic function increases the half-life of the drug by several hours, it is likely that
cefprozil undergoes a variety of metabolic transformations catalyzed by liver enzymes. For
each of the metabolic transformations A–F, identify which metabolic transformation has
occurred and whether the product formed was the result of a Phase I or Phase II metabolic
transformation.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 367
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Name of Transformation Phase I or Phase II
A
B
C
D
E
F
8. Like the penicillins, the cephalosporins suffer from chemical instability of the β-lactam
bond. Chemical hydrolysis of this bond renders the drug inactive. This bond is also subject to cleavage by β-lactamases (due to the presence of a nucleophilic serine side chain
[CH
OH] within the active site of the enzyme). Show how the β-lactam bond can be hydro-
2
lyzed by chemical and enzymatic (β-lactamase) mechanisms.
LEVONORGESTREL (LEVEL 3)
Levonorgestrel is a first-generation progestin that is a component of several contraceptive methods. Alone, as well as when paired with estrogen, levonorgestrel is an effective oral contraceptive.
This hormone combination is also available as a patch. Levonorgestrel is the active ingredient in an
intrauterine device (IUD), in an implantable contraceptive, and as a component of Plan B emergency
contraception.
1. Consider only the boxed functional groups found in levonorgestrel and complete the
grid below. Reminder: When we use the term solubility, we think about aqueous solubility whereas when we use the term absorption, we think about the ability of a drug to be
absorbed across a lipid bilayer.
368 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Function: Contribute to
Name of Functional
Group
A
B
C
D
E
Character: Hydrophobic,
Hydrophilic, or Both
Aqueous Solubility or
Absorption
2. In Chapter 2 we discussed that the electronic effect of a functional group is measured by
its ability to either donate its electrons to adjacent atoms or functional groups or pull or
withdraw electrons away from adjacent atoms or functional groups. Describe the electronic
effect of two of the functional groups (A and E) in levonorgestrel. (HINT: Remember to
consider both inductive and resonance effects!)
3. Consider your answers to Questions 1 and 2 and the information presented in Figures 2-12
and 2-13 and provide a structural rationale for why levonorgestrel can be administered
orally as well as via a patch-based formulation.
4. Is levonorgestrel an electrolyte or a nonelectrolyte? Provide a brief structural rationale for
your answer.
5. Levonorgestrel undergoes extensive protein binding by sex hormone binding globulin
(48%) and albumin (50%). Provide a structural rationale for why levonorgestrel is bound
to albumin.
6. In Chapter 5, we learned that functional groups have an influence on the partition coefficient of a drug molecule. We know that levonorgestrel can be administered orally (log
P = 3.8). An orally available prodrug of levonorgestrel (norgestimate) is also available (log
P = 4.11).
A. Based on your knowledge of how structure influences log P, what type of structural
modification to levonorgestrel would cause the log P value to decrease?
B. From a drug solubility perspective, did your proposed structural modification enhance
water solubility or lipid solubility?
C. Compared with levonorgestrel, is norgestimate more water soluble or lipid soluble?
Provide a structural rationale for this change in log P.
7. The progesterone receptor contains a hydrophobic cavity in which the receptor agonist
interacts. The estrogen receptor contains a similar cavity but also requires the natural hormone to have an aromatic A ring (flat) and to interact via two critical H-bonding interactions that are a specific distance apart. Shown here is ethinyl estradiol, an orally active
CH 10 - WHOLE MOLECULE DRUG EVALUATION 369
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estrogen agonist. Provide a struct ural rationale for why levonorgestrel is an agonist at both
the progesterone and estrogen receptors.
8. In Chapter 7 you learned about different types of isomers. Although marketed as a racemic
mixture, levonorgestrel is the only active isomer. For levonorgestrel to bind and activate
the progesterone receptor, the steroid ring system must be in an all trans configuration to
remain relatively flat.
A. What kind of isomer is the trans referring to?
B. Box all of the trans relationships in levonorgestrel.
C. The structures below represent saturated analogs of levonorgestrel (the double bond
in the A ring has been reduced). Evaluate the structures below and box the functional
groups that are in the cis configuration.
D. Predict whether the steroid skeleton would be able to adopt the shape necessary to
allow for interactions with the hydrophobic cavity found in the progesterone receptor
and the H-bonding interactions with the estrogen receptor if a mixed cis/trans configuration was present.
9. Levonorgestrel does not undergo first pass metabolism and is 100% bioavailable, which
you might find somewhat surprising.
A. Describe first-pass metabolism and the types of molecules that are typically subject
to it.
370 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
B. Provide a structural rationale for why you might expect levonorgestrel to exhibit first-
pass metabolism.
C. Identify which Phase I and II metabolic transformations are possible.
MONTELUKAST AND ZAFIRLUKAST
Shown below are the structures of montelukast and zafirlukast. These drug molecules are administered orally for the treatment of asthma and allergic rhinitis.
1. The structure of montelukast contains one acidic functional group (pKa = 4.4) and one basic
functional group (pKa = 3.1), whereas the structure of zafirlukast only contains one acidic
functional group (pKa = 4.3). Identify these acidic and basic functional groups and predict
whether they will be primarily ionized or primarily unionized at a stomach pH of 1.9, a urine
pH of 5.4, a cellular pH of 6.1, a plasma pH of 7.2, and a solution pH of 8.3.
Functional
Group
Acidic or
Basic
1.9 5.4 6.1 7.2 8.3
Primarily Ionized or Unionized
2. In the previous question, we examined three pKa values in five different environments for
a total of 15 different scenarios. Which of these 15 scenarios allow you to use the Rule of
Nines to calculate the percent of ionization of the functional group in the specific environment? Identify the specific scenarios and use the Rule of Nines to calculate the percent of
the functional group that would be ionized.
3. The normal pKa range for sulfonamides is 5 to 10. The pKa value for the sulfonamide present
within the structure of zafirlukast is 4.3. Conduct a structural analysis and provide a reason
why this pKa value is lower than the normal range.
4. The sodium salt of montelukast is required for its oral administration whereas zafirlukast
can be administered orally as its unionized free acid form. Conduct a structural analysis of
these two drug molecules and provide an explanation for this difference.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 371
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5. Montelukast and zafirlukast exert their mechanism of action by interacting with cysteinyl
leukotriene receptors and blocking the normal actions of endogenous leukotrienes (LTC4,
LTD4, and LTE4). It has been proposed that this interaction requires five key elements: an
ionic bond, a hydrogen bond interaction in which the antagonist acts as the acceptor, and
the interaction of the antagonist with three separate hydrophobic pockets within the
receptor. Using this information and the structures of montelukast and zafirlukast, propose potential binding interactions between these drug molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a physiologic pH of 7.4.
6. Evaluate the structures of montelukast and zafirlukast and determine if they can have
enantiomers, diastereomers, geometric isomers, and/or conformational isomers.
7. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the computer program used to predict these values. Given this information, would
these drug molecules be predicted to be highly plasma protein bound or minimally plasma
protein bound? Additionally, would you expect these drug molecules to undergo extensive
hepatic metabolism or be primarily excreted unchanged?
Shown below are four known metabolites of montelukast. Identify the metabolic transfor-
8.
mations that are required to produce these metabolites. For each transformation, identify
if it is a Phase I transformation or a Phase II transformation.
372 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
9. Shown below is the structure of zafirlukast and a list of five metabolic transformations.
For each metabolic transformation, indicate if it is a Phase I or a Phase II transformation
and if zafirlukast has a functional group present to participate in the transformation. If
you answer YES, then draw the appropriate metabolite; if you answer NO, then provide a
brief explanation as to why this metabolic transformation is not possible to perform with
zafirlukast.
Metabolic Pathways
A. Methylation
B. Aromatic oxidation
C. Hydrolysis
D. Oxidative O-dealkylation
E. Benzylic oxidation
NADOLOL AND OTHER a-ADRENERGIC
ANTAGONISTS (LEVEL 3)
Shown below is the structure of nadolol, a β-adrenergic receptor antagonist (aka a β blocker) that
is used to treat hypertension and angina. Please note that the stereochemical designations of chiral centers have been purposefully omitted for the first two questions. The SAR of β-adrenergic
agonists and antagonists was briefly discussed in Chapter 9, and this information may be helpful in
conducting a structural evaluation for some of the questions.
1. Using the table below, identify the six boxed functional groups. For each of the functional
groups you identify, indicate if it is primarily hydrophilic or hydrophobic in character. Also
provide a brief explanation for your response.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 373
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Functional Group Name Hydrophilic or Hydrophobic
A
B
C
D
E
F
2. Epinephrine is a naturally occurring hormone that is secreted by the medulla of the adrenal glands. It plays a role in the “fight or flight” response and acts as an agonist at the
β-adrenergic receptors. Compare the structures of nadolol and epinephrine and provide an
explanation as to why nadolol is able to act as a β-adrenergic receptor antagonist.
3. The structure of nadolol contains three chiral centers; however, the two hydroxyl groups
in the bicyclic tetrahydronaphthylene (aka tetralin) ring are always in a cis configuration.
Nadolol is marketed as a pair of racemates as shown below. Two of these stereoisomers
exhibit superior binding interactions with the β-adrenergic receptor while the other two do
not. Using these structures as well as the structure of epinephrine, identify the more active
stereoisomers and provide an explanation for your choice.
4. In examining the β blocker class of drugs, nadolol has the lowest oral absorption (30%) and
the second lowest log P value (1.3). Given this information, what chemical strategies could
be used to enhance the oral absorption of nadolol?
5. Nadolol is a nonselective β blocker. Its actions at the β1-adrenergic receptor are responsible for its beneficial effects in hypertension and angina; however, its actions at the
β
-adrenergic receptor are responsible for certain adverse effects, such as bronchoconstric-
2
tion. Atenolol (shown below) is a selective β1 blocker and is often preferred over nadolol
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