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384 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
5. The structure of saquinavir contains six chiral centers that have been circled below. Provide
an explanation why the alteration of the stereochemistry at any of these chiral centers
could lead to a decrease in the ability to inhibit HIV protease.
6. Fosamprenavir calcium, shown below, is an orally administered prodrug of amprenavir.
Using the structure and name of fosamprenavir, identify the metabolic transformation
that is required to convert it to amprenavir, draw the structure of amprenavir, and provide
potential advantages for using this prodrug.
7. All HIV protease inhibitors contain similar, but not identical, structural features. Compare
the structures of saquinavir and amprenavir and identify the structural similarities that
allow both of these drugs to bind to the same enzyme. Your answer should include potential binding interactions of these two drugs.
8. Ritonavir is also used to treat HIV infections; however, due to its adverse effects profile,
it is rarely used at therapeutic doses. Instead, it is used as a pharmacokinetic enhancer.
Ritonavir is both a substrate and an inhibitor of CYP3A4. The ability to inhibit CYP3A4
prevents the metabolism of other HIV protease inhibitors and enhances their actions.
Shown below are four possible metabolic pathways for ritonavir. For each pathway, identify the metabolic transformation involved and indicate whether it could be catalyzed by
the CYP3A4 isozyme.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 385
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9. Shown below is darunavir, a structural analog of amprenavir, and one of its possible metabolites. Identify the metabolic transformations that would be required to convert darunavir
to this metabolite.
386 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
SORAFENIB (LEVEL 2)
Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is
no surprise that several neoplastic disorders can be tied to altered protein tyrosine kinase activity. Clinically relevant antineoplastic tyrosine kinase inhibitors interact with the active site of the
enzyme via several types of binding interactions. The adenosine triphosphate (ATP) binding domain
of the tyrosine kinases contains a hydrophobic domain that includes a significant number of isoleucine, leucine, alanine, and valine residues. At least five binding pockets flank this region in which van
der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib is a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a
hig hly vascularized tumor. The drug specifically targets vascular endothelin growth factor 2 (VEGF2),
which is instrumental in the generation of new blood vessels.
1. Conduct a structural evaluation of sorafenib, focusing on the boxed functional groups, and
use the information in the grid to inform your answers to the questions that follow.
Interaction(s)
Possible with
Name of
Functional
Group
A
B
C
D
E
F
2. Sorafenib interacts with Cys
Hydrophilic
and/or
Hydrophobic
919
1047
, Phe
Acidic, Basic,
or Neutral
(Provide pKa
When Relevant)
, and Asp
1046
via hydrogen bonding and hydrophobic
Contributes
to Aqueous
Solubility and/
or Absorption
Biological
Target at
Physiologic
pH = 7.4
interactions. Identify which functional groups could interact with the side chains of these
amino acids. Assume that Asp
1046
is unionized in the local environment of the enzyme.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 387
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Functional Group
Interacts with
Cysteine
Hydrogen Bonding
Interaction
919
via a
Interacts with Aspartic
1046
via a Hydrogen
Acid
Bonding Interaction
Interacts with
Phenylalanine
1047
via a
Hydrophobic Interaction
Yes or No Yes or No Yes or No
A
B
C
D
E
F
3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of
Philadelphia Chromosome (Ph+) positive chronic myelogenous leukemia, also interacts
with each of the five binding pockets found within this biological target. This drug interacts with Leu
/Val
, Asp
/Glu
, Thr
, Met
318
, and Leu
298
/Val
299
/Phe
359
in each of the
285
289
391
286
315
respective five binding pockets.
A. Consider the side chains of the amino acids indicated and determine which type(s)
of binding interactions is/are possible in each of the five binding pockets. Assume
pH = 7.4.
285
Leu
/Val
289
Asp
391
/Glu
286
Thr
315
Met
318
Leu
298
299
/Val
/Phe
B. Determine which of the boxed functional groups (A–E) can interact with the side
chains of the amino acids found in each of the five binding pockets. Indicate the type of
interaction(s) possible in the appropriate box. “None” is an acceptable answer. Assume
that the drug and the amino acid side chains are both at pH = 7.4.
285
Leu
/Val
289
Asp
391
/Glu
286
Thr
315
Met
318
Leu
298
/Val
299
/Phe
A
B
C
D
E
359
359
388 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
C. It has been documented that the pyridyl nitrogen atom (functional group E) of nilotinib
participates in a hydrogen bonding interaction with methionine. Draw a diagram that
clearly shows which atom(s) within the structure of methionine participate in this
interaction.
4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a starting point, identify which functional groups contribute to the ability of
this drug to enter cells via passive diffusion.
5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is 2.4 and 0.8, respectively). Provide a structural rationale for this property
difference.
6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as
a hydrochloride monohydrate salt, an inorganic salt. In general, what is the value of each
of these types of salts?
7. At least 50% and 69% of a sorafenib and nilotinib dose, respectively, are eliminated fecally.
Both drugs undergo CYP3A4 mediated oxidation. List ALL possible Phase I metabolic transformations that represent oxidative transformations for each drug.
8. Both drugs are more than 99.5% plasma protein bound, primarily to serum albumin. While
bound to albumin, is it possible for either of these drugs to be metabolized or eliminated or
interact with their respect biological targets?
ZANAMIVIR AND OSELTAMIVIR (LEVEL 2)
Shown below is the structure of zanamivir. This drug molecule is administered via oral inhalation for
the treatment of influenza A and B infections.
1. Identify all of the acidic and basic functional groups, provide the normal pKa range for each
functional group and identify whether each functional group would be primarily ionized or
unionized at a pulmonary pH of 7.2.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 389
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2. Identify all other water-soluble functional groups that are present within the structure of
zanamivir.
3. Based on your answers to Questions 1 and 2, explain why zanamivir is administered as an
oral inhaler instead of an oral tablet or capsule.
4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is
required for the spread of the viral infection. A key component of neuraminidase’s action
is the hydrolysis of N-acetylsialic acid from surface viral glycoproteins. Shown below is
the structure of N-acetylsialic acid bound to a glycoprotein. Using this structure and the
structure of zanamivir, provide an explanation for how zanamivir inhibits neuraminidase.
5. Oseltamivir is a structural analog of zanamivir. It has the same mechanism of action of zanamivir but differs in that it can be administered as either an oral capsule or oral suspension.
Conduct a structural comparison of oseltamivir and zanamivir and provide an explanation
of why oseltamivir is better suited for oral administration.
6. The pKa of the primary amine found within the structure of oseltamivir has been reported
to be 7.7. What percent of this functional group is ionized at an intestinal pH of 6.5?
7. Shown below is a stereoisomer of zanamivir. Identify if the stereoisomer is an enantiomer,
a diastereomer, a geometric isomer, an epimer, and/or a conformational isomer. Predict
whether this stereoisomer’s pharmacological activity is likely to be more active, less active,
or similar to that of zanamivir.
390 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
8. Shown below is the structure of oseltamivir and a list of five metabolic transformations.
For each metabolic transformation, indicate whether it is a Phase I or Phase II transformation and whether oseltamivir has a functional group present that can undergo the indicated
transformation. When evaluating these metabolic transformations, consider functional
groups that are initially present within the structure of oseltamivir as well as those that can
be added/revealed through Phase I metabolism. 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 oseltamivir.
Metabolic Pathways
A. Hydrolysis
B. Allylic oxidation
C. Glucuronide conjugation
D. ω-Oxidation
E. Oxidative O-dealkylation
9. Using the information discussed in previous questions, provide an explanation why zanamivir is not metabolized and is excreted unchanged in the urine.
ANSWERS TO
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CHAPTER QUESTIONS
CHAPTER 2
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
1. Answers provided in table below.
Functional Group Name
A Halogen (chlorine atom) Lipid solubility
B Alicyclic ring, alkyl ring, cycloalkane Lipid solubility
C Tertiary amine (piperazine) Water solubility
D Heterocyclic ring system (pyrrolopyridine) Hydrocarbons: lipid solubility
E Aromatic ring; phenyl ring; aromatic hydrocarbon Lipid solubility
F Sulfonamide Water solubility
G Secondary aromatic amine/aniline Water solubility
H Ether Hydrocarbons: lipid solubility
APPENDIX
Contribution to Water and/or
Lipid Solubility
Nitrogen atoms: water solubility
Oxygen atom: water solubility
2. The sulfonamide and tertiary amine are primarily ionized in most physiologic environments
and can participate in ion–dipole interactions (as the ion) with water. In the event that they
are unionized, they could participate in hydrogen bonding interactions with water. The
nitrogen atoms of the heterocyclic ring system, as well as the secondary aromatic amine,
and the oxygen atom of the ether will not be appreciably ionized but can participate in
hydrogen bonding interactions with water. Thus, all of these functional groups contribute
to the water solubility of venetoclax. The halogen as well as the hydrocarbon chains and
rings are not able to ionize or form hydrogen bonds with water and thus contribute to the
lipid solubility of venetoclax.
DOI 10.37573/9781585286959.0 11
391
392 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Answers provided in table below.
Electron Donating or
Withdrawing Resonance or Induction
A Electron withdrawing Induction
B Both Donates electrons into the aromatic ring through resonance
C Electron donating Resonance
D Electron withdrawing Induction (from aromatic ring)
E Electron withdrawing Resonance
Checkpoint Drug 2: Elamipretide
1. Answers provided in the grid below.
Withdraws electrons from adjacent methylene groups
through induction
Resonance (from ionized sulfonamide)
Character: Hydrophobic,
Name of Functional Group
A Guanidine Hydrophobic (R) Absorption (R)
B Primary amine Hydrophobic (R) Absorption (R)
C Amide Hydrophobic (R) Absorption (R)
D Aromatic hydrocarbon; aromatic ring;
phenyl ring
E Phenol Hydrophobic (R) Absorption (R)
R = carbon scaffolding.
Hydrophilic, or both
Hydrophilic (H2NCNHNH) Solubility (H2NCNHNH)
Hydrophilic (NH2) Solubility (NH2)
Hydrophilic (C=ONH2) Solubility (C=ONH2)
Hydrophobic (R) Absorption (R)
Hydrophilic (OH) Solubility (OH)
Function: Contribute to
Solubility or Absorption
2. Part A: Every amino acid has an amine (basic), a unique side chain, and a carboxylic acid
(acidic). As building blocks of proteins, the amine and carboxylic acid of adjacent amino
acids are linked to form an amide or peptide linkage (neutral).
Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and
carboxylic acid of adjacent amino acids are linked to form a peptide bond (amide = neutral).
The easiest way to read these kinds of molecules is to look for the pattern “amine-side
chain-carbonyl” (representing one amino acid) and to completely ignore the fact that the
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 393
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amine and adjacent carboxylic acid are really an amide. In the diagram below, the “amineside chain-carbonyl” pattern for the first two amino acids/amino acid derivatives is shown.
Using this pattern, the first amino acid in the sequence is the amino acid arginine, the
second amino acid is a derivative of tyrosine, the third amino acid is lysine, and the fourth
amino acid is phenylalanine.
Part C: The portions of the molecule that represent arginine, lysine, and phenylalanine have
been boxed.
Part D: The second amino acid is a derivative of tyrosine.
3. Answers provided in the grid below.
Amino Acid Side
Name of Amino
Acid or Amino Acid
Derivative
1 Arginine Hydrophilic (NHC=NHNH2) Basic NA
2 Tyrosine derivative Hydrophilic (OH) Acidic Nucleophilic
3 Lysine Hydrophilic (NH
4 Phenylalanine Hydrophobic Neutral NA
R = carbon scaffolding.
Amino Acid Side Chain
Evaluation: Hydrophobic,
Hydrophilic, or Both
Hydrophobic (R)
Hydrophobic (R)
) Basic Nucleophilic
2
Hydrophobic (R)
Chain Evaluation:
Acidic, Basic,
Neutral
Amino Acid Side
Chain Evaluation:
Nucleophilic,
Electrophilic, NA
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