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374 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
and other nonselective β blockers. Compare the structures of nadolol (isomer B-1) and
atenolol and offer an explanation why atenolol is selective for the β1-adrenergic receptor
and nadolol is not.
6. Using the table below, identify the types of binding interactions that could be possible
between the boxed functional groups on atenolol and the β1-adrenergic receptor. Also identify amino acids present within a protein receptor whose side chains could participate in the
interactions that you identified. Assume a plasma pH = 7.4 for all ionizable functional groups.
Amino Acids Capable
Types of Binding
Functional Group
A
B
C
D
E
Interactions
of Forming Specific
Binding Interactions
7. Shown below is the structure of propranolol, a nonselective β blocker similar to nadolol.
In comparing these two drugs, it is found that one of these undergoes extensive first-pass
metabolism while the other is essentially eliminated unchanged. Additionally, one of these
drugs can be used to treat central nervous system (CNS) disorders such as anxiety and prophylactic prevention of migraine headaches while the other cannot. Conduct a structural
analysis of these two drugs and identify which drug undergoes first-pass metabolism and
which drug can be used for CNS disorders.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 375
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8. The following questions pertain to acebutolol, a selective β1 blocker similar to atenolol.
A. Diacetolol is an active metabolite of acebutolol. What metabolic pathways are required
to convert acebutolol to diacetolol?
B. Shown below is a list of five metabolic transformations. For each metabolic transfor-
mation, indicate if it is a Phase I or a Phase II transformation and if the structure of
acebutolol has a functional group that can undergo the indicated transformation. For
the purposes of this question, only consider the functional groups that are initially
present within the structure of acebutolol. 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 for acebutolol.
Metabolic Pathways
A. Oxidative deamination
B. Reduction
C. Benzylic oxidation
D. Oxidative O-dealkylation
E. Sulfate conjugation
9. Esmolol is similar in structure to both acebutolol and atenolol and is a selective β1 blocker.
It is unique in that it has an extremely short duration of action and must be used as a continuous intravenous (IV) infusion. Esmolol is useful in the acute control of hypertension and
in the treatment of certain supraventricular arrhythmias. Identify the metabolic pathway
that rapidly inactivates esmolol, draw the product of this reaction, and provide an explanation as to why the metabolite is inactive.
376 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
OFLOXACIN (LEVEL 1)
Ofloxacin is a synthetic antibacterial agent and is a member of the second generation of fluoroquinolones. It is formulated as an oral tablet, an eye drop (to treat pink eye), and an ear drop (to treat
otitis media) and can be administered by IV route to treat both gram (+) and gram (–) infections. As
an oral tablet or IV solution, it is typically used in the treatment of bronchitis; community-acquired
pneumonia; infections of the cervix, urethra, and urinary tract; and prostatitis.
1. First, we need to conduct a thorough structural evaluation of ofloxacin so that we can
explore the different routes of administration. Complete the grid below to start the structure evaluation process. 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.
Name of Functional
Group
A
B
C
D
E
F
G
Hydrophobic and/or
Hydrophilic
Contributes to Aqueous
Solubility and/or Absorption
2. Considering the boxed functional groups found in ofloxacin, which of the functional groups
are best described by the following terms. HINT: You may need to consider inductive and
resonance effects for some of these terms.
A. Electron withdrawing group
B. Electrophilic functional group
CH 10 - WHOLE MOLECULE DRUG EVALUATION 377
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C. Nucleophilic functional group
D. Electron donating group
3. Ofloxacin has several pKa values. Complete the table below to provide structural evidence
for this. Determine if ofloxacin is an electrolyte, a nonelectrolyte, or is amphoteric.
Name of Functional
Group
A
B
C
D
E
F
G
Acidic, Basic,
or Neutral pK
Value/Range
a
4. As an oral tablet, ofloxacin has 98% oral bioavailability, is 65% to 80% excreted unchanged
in the urine, and is 32% protein bound. Consider only the acidic and basic functional groups
in each pH environment and, using a qualitative approach, determine if each functional
group is predominantly ionized or unionized in each pH environment.
Name of
Functional Group pH = 2 (Stomach) pH = 7.4 (Plasma) pH = 5 (Urine)
pH = 8.5
(Large Intestine)
A. Provide a brief structural rationale for why ofloxacin is largely excreted unchanged in
the urine.
B. Provide a brief structural rationale for why ofloxacin can be formulated as an aqueous
solution (pH = 6.5), as an eye drop, and as an ear drop.
5. Drugs are often formulated in a modified form to improve aqueous or lipid solubility.
A. Determine if ofloxacin can be formulated as a sodium salt and/or as a hydrochloride salt.
Modify the structure to show the possible inorganic salt form(s) of the drug and determine whether this modification will improve the aqueous or lipid solubility of the drug.
B. What kind of structural modification could be made to ofloxacin to improve its lipid
solubility?
6. Four molecules of the fluoroquinolone antibacterial agents interact with bacterial DNA via
interactions with functional groups along the top of the molecule. There are also drug-drug
self-association interactions along the lower half of the molecule. The molecules themselves are oriented in two pairs.
378 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
A. Consider the functional groups on the top half of the molecule. What kind of interac-
tions could those functional groups participate in with the bacterial DNA?
B. Consider the functional groups on the bottom half of the molecule. What kind of inter-
actions could those functional groups have between each pair of molecules as part of
the drug-drug self-association interactions?
C. Consider the core of the molecule (functional groups that the line is drawn through.
What type of interaction is likely to be occurring to keep two molecules paired together?
7. Ofloxacin is marketed as a racemate. Levofloxacin is the active isomer. There has been no
effort to market only the active isomer.
A. Circle the chiral center(s) in ofloxacin.
B. Which of the following isomers are possible: enantiomers, diastereomers, geometric
isomers, conformational isomers?
C. Given the location of the chiral carbon(s), determine which interactions (drug–target
or drug–drug) are impacted by chirality.
8. Ofloxacin has 98% oral bioavailability and is primary eliminated unchanged via a renal
route. A small portion of each does undergoes metabolism in the liver and is eliminated via
a fecal route.
A. Does ofloxacin undergo first-pass metabolism?
B. List all possible Phase I and Phase II transformations.
C. Based on your knowledge about ofloxacin excretion, in which patients is ofloxacin
likely to be contraindicated?
PRAVASTATIN AND FLUVASTATIN (LEVEL 2)
Shown below are the structures of pravastatin and fluvastatin. These drug molecules are used in
the treatment of various types of hyperlipidemia/dyslipidemia. A total of six functional groups have
been boxed.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 379
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1. Using the table below, identify the six boxed functional groups. For each of the functional
groups you identify, indicate if it is hydrophilic or hydrophobic in character. Also provide a
brief explanation for your response.
Functional Group Name Hydrophilic or Hydrophobic
A
B
C
D
E
F
2. The log P values of pravastatin and fluvastatin are 1.44 and 3.62, respectively. Conduct a
structural analysis of these drug molecules and provide a structural explanation for the
difference in these log P values.
3. The normal pKa range for carboxylic acids is 2.5 to 5. The pKa values for the carboxylic acids
present within the structures of pravastatin and fluvastatin are 4.21 and 4.56, respectively.
Conduct a structural analysis of these drugs and provide a plausible reason why these pKa
values are at the high end of the normal range.
4. Using the pKa value of fluvastatin (4.56), calculate the percent of fluvastatin that would be
unionized in a urine pH of 5.20.
5. Although the Rule of Nines cannot be used to solve Question 4, it can be used to help verify
that the answer obtained using the Henderson-Hasselbalch equation is correct. How would
you use the Rule of Nines to help verify your answer to question 5?
6. Pravastatin and fluvastatin exert their hyperlipidemic effects by inhibiting the enzyme
HMG CoA reductase. As shown below, HMG CoA reductase converts 3-hydroxy3-methylglutaryl CoA (HMG CoA) to mevalonic acid. This conversion is required for the
synthesis of cholesterol and acts as a primary control site for production of this endogenous steroid. Using the structures of HMG CoA, mevalonic acid, pravastatin, and fluvastatin, provide a structural explanation as to how pravastatin and fluvastatin inhibit HMG
CoA reductase.
7. Shown below are the structures of fluvastatin and a conformationally restricted analog.
The conformational restriction results from the addition of a carbon atom and a double
bond and essentially abolishes the therapeutic activity of fluvastatin. Using these structures, postulate a reason why this structural change results in a loss in activity.
380 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
8. Shown below is a known metabolite of fluvastatin. Identify the metabolic transformations
required to produce this metabolite.
9. Pravastatin is primarily metabolized to its 3α epimer.
This metabolite is completely inactive as an HMG
CoA reductase inhibitor. Identify the metabolic
transformations required to produce this metabolite
and provide an explanation as to why this metabolite
is inactive.
QUINAPRIL (LEVEL 1)
Shown below is the structure of quinapril. It is an angiotensin-converting enzyme (ACE) inhibitor
that is used in the treatment of hypertension and heart failure. Five functional groups are identified.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 381
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1. Using the table below, identify the five boxed functional groups. For each of the functional
groups you identified, indicate if it is hydrophilic or hydrophobic in character. Also provide
a brief explanation for your response.
Solubility Effect of
Functional Group Name
A
B
C
D
E
Functional Group
2. Using the unmodified structure of quinapril and the table below, identify all of the acidic
and basic functional groups present in the structure, provide the normal pKa range for each
functional group, and identify if each functional group would be primarily ionized or union-
ized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
Functional
Group
Acidic or
Basic pK
Range
a
1.5 4.8 6.3 7.4 8.1
Primarily Ionized or Unionized
3. Quinapril is a prodrug. It is administered as an oral tablet and converted in vivo to its active
metabolite, quinaprilat. Identify the metabolic pathway that converts quinapril to quinaprilat and offer a reason why quinapril is administered orally instead of quinaprilat.
4. Quinapril inhibits ACE. This enzyme is a relatively nonspecific dipeptidyl carboxypeptidase.
It is a zinc protease that converts angiotensin I, a decapeptide, to angiotensin II, an octapeptide. The peptide cleavage is catalyzed by the zinc atom and is shown below. Quinapril,
382 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
along with other ACE inhibitors, is a tripeptide mimic that can interact with the enzyme,
resulting in enzyme inhibition rather than hydrolysis. Using this information and the structures provided below, identify how quinapril can interact with ACE. Assume that all drug
binding interactions are occurring at a pH of 7.4.
5. Shown below are four possible metabolic pathways for quinapril. Identify the metabolic
transformations involved in these pathways.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 383
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6. Although it is possible for quinapril to undergo all of the above metabolic transformations,
pathway B is the major pathway. Other metabolites have been identified but only at very
low levels. Provide an explanation for this finding.
7. In evaluating the overall structure of quinapril, identify if it is an acidic drug molecule, a
basic drug molecule, an amphoteric drug molecule, or a nonelectrolyte.
8. Shown below is a stereoisomer that is significantly less active than quinaliprat. Identify if
the stereoisomer is an enantiomer, a diastereomer, a geometric isomer, an epimer, and/or
a conformational isomer. Additionally, provide an explanation as to why this isomer is less
active.
SAQUINAVIR AND OTHER HUMAN IMMUNODEFICIENCY
VIRUS PROTEASE INHIBITORS (LEVEL 3)
Shown below is the structure of saquinavir, an antiviral drug used to treat human immunodeficiency
virus (HIV) infections.
1. Identify the most acidic or basic functional group within the structure of saquinavir, provide the normal pKa range for this functional group, and identify if it would be primarily
ionized or unionized at a gastric pH of 2.3.
2. Using the functional group you identified in the previous question, draw a water-soluble
organic salt. What potential therapeutic benefits would this salt provide?
3. Identify the functional groups present within the structure of saquinavir that allow it to
pass through GI membranes and become absorbed into the systemic circulation.
4. Saquinavir inhibits HIV protease, a viral enzyme that cleaves viral precursor proteins into
mature, active proteins. As part of its mechanism, HIV protease uses a pair of aspartic acid
residues to catalyze the cleavage of a peptide bond between phenylalanine and proline as
shown below. HIV protease can also cleave peptide bonds between tyrosine and proline.
Using this information and the structure of saquinavir, provide an explanation how saquinavir inhibits HIV protease.
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