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464 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
a prodrug, must undergo a Phase I metabolic transformation (ester hydrolysis) to “reveal”
the underlying ionizable carboxylic acid.
Part B: The active form of fenofibrate (carboxylic acid) contains a para chloro substituent
on the aromatic hydrocarbon. Fibrates with a para chloro substituent have a significantly
longer half-life than those that do not have a para chloro substituent or chloro containing
substituent.
10. A check mark or comment has been included in the table to indicate if the drug molecule
follows the SAR.
Epoprostenol (PGI2) Iloprost Treprostinil
C-1 carboxylic acid to
participate in required ionic
or ion/dipole interaction
C-11 and C-15 hydroxyl groups
to participate in H-bonding
interactions
Cyclopentane ring system + C-5
and C-13 double bonds
(to maintain geometry)
C-6 oxygen (increases potency
and undergoes rapid
metabolism to inactive drug)
Additional functional groups
capable of H-bonding
interactions (decreases
receptor affinity)
✓ ✓ ✓
✓ ✓ ✓
✓ ✓
✓
Not present Not present Not present
Not present Not present
Cyclopentane ring
present; C-5 double
bond replaced
by aromatic
hydrocarbon
11. Part A: The replacement of the secondary aromatic amine with a methylene group is an
example of a classic divalent isosteric modification. Although the size of a methylene group
is similar to that of a secondary amine, its solubility and electronic properties are very different. The secondary aromatic amine is more water soluble than the methylene group
and can participate in hydrogen bonds (as both a donor and an acceptor), ion-dipole bonds
(as the dipole), and dipole-dipole bonds. Additionally, the lone pair of electrons on this
amine can contribute to resonance through its ability to donate electrons into the two
adjacent aromatic rings. In contrast, the methylene group is more lipid soluble and cannot
form hydrogen bonds, ion-dipole bonds, or dipole-dipole bonds. It can participate in van
der Waals interactions; however, this binding interaction is very different from that of the
original secondary aromatic amine. Therefore, this isosteric change would be expected to
alter the ability of dasatinib to interact with/bind to its biological target.
Part B: The replacement of a chloro group with a methyl group is an example of a classic
monovalent isosteric modification. As discussed in Chapter 8, aromatic rings with electron withdrawing groups (such as the chloro group) are less likely to undergo aromatic
oxidation than are unsubstituted rings or those with electron donating groups (such as a
methyl group). Therefore, this isosteric change would most likely lead to an increase in aromatic hydroxylation, which could then be followed by Phase II conjugation. Additionally,
this isosteric change adds a methyl group that can easily be oxidized to either a benzylic
hydroxyl group or a carboxylic acid. The removal of the electron withdrawing chloro group
also makes the other ortho methyl group more susceptible to oxidation. In summary, this
isosteric change would be expected to increase the rate of metabolism of dasatinib and
decrease its duration of action.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 465
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12. Part A: The initials SAR represent a Structural Activity Relationship, a term that literally
defines the relationship between the chemical structure of a drug molecule and the physiologic, pharmacological, pharmacokinetic, and therapeutic effects it provides. The structure of a drug molecule refers to its functional groups and their stereochemical orientation
to one another. The activity of a drug molecule can refer to its pharmacological actions, its
route of administration, its ability to bind to specific receptors, its ability to be metabolized
by a specific pathway (or not), its duration of action, and/or its ability to cause specific drug
interactions or adverse effects.
Part B: The most important component of any SAR is the why or how component. Without
this component, an SAR simply becomes something to memorize. Stating that “Drug A has
a higher affinity for its target receptor than any other drug in its pharmacological class”
does not allow for any application, nor does it provide any information to design any additional drugs. An example of a more complete, and proper, SAR would state, “The structure
of Drug A contains a hydrogen bond acceptor meta to the acidic functional group on the
aromatic ring. This greatly enhances the affinity of Drug A for its target receptor.”
CHAPTER 10
Aliskiren (Level 1)
1. Functional group names and other information provided below.
Function:
Amino Acids
Character:
Acidic,
Basic, or
Neutral
Name of
Functional
Group
A Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A) Asp, Glu, Lys,
B Aromatic
hydrocarbon
C Aliphatic
alkane
D Primary amine Hydrophilic
E Secondary
alcohol
Character:
Hydrophilic and/
or Hydrophobic
Hydrophobic (R) Absorption (R) Dipole–dipole
Hydrophobic Neutral Absorption Hydrophobic None
Hydrophobic Neutral Absorption Hydrophobic None
(NH
)
2
Hydrophobic (R) Absorption (R) Ionic
Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A
Hydrophobic (R) Absorption (R) Dipole–dipole
(Provide
pK
When
a
Relevant)
Basic pK
∼9-11
Function:
Contribute
to Aqueous
Solubility and/
or Contribute
to Absorption
Solubility (NH2) Ion–dipole (as
a
Function:
Interaction(s)
Possible with
Biological
Target at
Physiologic
pH = 7.4
Ion–dipole (as
the dipole)
van der Waals
π-π stacking
van der Waals
the ion)
+ D)
Ion–dipole (as
the dipole)
That Can
Interact with
the Functional
Group via
Ion–Dipole
Interactions at
pH = 7.4
Ser, Thr, Cys, Tyr,
Asp, Glu, Lys,
a
Arg
Asn, Gln, His,
Trp, Met
Arg
466 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Character:
Acidic,
Basic, or
Neutral
Name of
Functional
Group
F Amide Hydrophilic
R = carbon scaffolding.
a
“None” is a possible answer.
Character:
Hydrophilic and/
or Hydrophobic
(CONH2)
Hydrophobic (R) Absorption (R) Dipole–dipole
(Provide
pKa When
Relevant)
Neutral Solubility
2. Chiral carbon atoms have been circled.
Function:
Contribute
to Aqueous
Solubility and/
or Contribute
to Absorption
(CONH2)
Function:
Amino Acids
Function:
Interaction(s)
Possible with
Biological
Target at
Physiologic
pH = 7.4
H-bonding (A) Asp, Glu, Lys,
Ion–dipole (as
the dipole)
That Can
Interact with
the Functional
Group via
Ion–Dipole
Interactions at
pH = 7.4
a
Arg
If there are two or more chiral carbon atoms, then it is possible for the drug to have dias-
tereomeric forms. In the case of aliskiren, there are four chiral carbon atoms; therefore,
there are a lot of potential diastereomeric forms. A quick reminder on how to determine
if a pair of isomers is diastereomeric: If one chiral carbon is held constant (e.g., R-isomer)
and you vary at least one additional chiral carbon, then the pair of isomers will be diastereomeric to one another. In the example below, the chiral center that is circled is held
constant and the (*) chiral center is varied. The pair of isomers drawn are diastereomers.
For geometric isomers to be possible, there must be restricted rotation around a carbon-
carbon bond (e.g., presence of a double bond or alicyclic ring). Evaluation of aliskiren reveals
the absence of double bonds and alicyclic rings; therefore, geometric isomers cannot exist.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 467
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3. Oral bioavailability depends on the drug’s ability to dissolve in the aqueous contents of the
gastrointestinal (GI) tract and its ability to cross the lipid bilayer membrane. The hydrophilic character of the drug promotes aqueous solubility. Evaluation of the entire molecule
(not just the boxed functional groups) for hydrophilic character reveals two ethers, two
amides, a primary amine (in its ionized form), and a secondary alcohol that contribute
meaningfully to the hydrophilic character of the drug. (N OTE: the drug is sold as a hemifumarate salt that further increases the overall water solubility of the drug). The hydrophobic
character of the drug promotes absorption across the lipid bilayer. Evaluation of the entire
molecule (not just the boxed functional groups) for hydrophobic character reveals an aromatic hydrocarbon, a lipophilic ether, and several aliphatic alkanes. The drug is formulated
as a water-soluble salt and has ample hydrophilic character. Unfortunately, it does not
have sufficient hydrophobic character to allow for meaningful absorption.
Metabolic transformations and identification of oxidative or nonoxidative provided below.
4.
Name of Metabolic Transformation Oxidative or Nonoxidative
A Oxidative O-dealkylation Oxidative
B Alcohol oxidation Oxidative
C Oxidative deamination Oxidative
D Oxidative O-dealkylation
E Amide hydrolysis
a
This metabolite has been identified as one of the two primary metabolites produced.
a
a
Oxidative
Non-oxidative
5. Functional groups mimicking Leu and Val are circled. The nonhydrolyzable hydroxyethylene group is boxed.
6. It is important to first determine whether these drugs are basic, acidic, or amphoteric
in nature. Based on a structural evaluation of the entire aliskiren molecule (not just the
boxed functional groups), there is one basic functional group (primary amine) and no acidic
functional groups present. The same evaluation for amlodipine yields identification of two
basic functional groups (primary amine and dihydropyridine ring) and no acidic functional
groups. Based on this evaluation, both drugs are basic, and both would be bound to α1-acid
glycoprotein (plasma protein). It is important to remember that plasma protein binding
interactions are likely to happen when a drug is > 90% plasma protein bound. Given the
extent to which amlodipine is plasma protein bound, it is highly likely that a plasma protein
binding interaction will occur when aliskiren displaces amlodipine from the glycoprotein
binding site. When this type of interaction occurs, there is a greater fraction of amlodipine
present in its unbound form. This leads to an increase in pharmacological activity, resulting
in hypotension (excessively low blood pressure).
468 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Aripiprazole (Level 1)
1. Acidic and basic function groups are identified along with ranges and ionization state at
pH = 5.6.
2. All other functional groups are identified along with their water or lipid nature.
3. The tertiary amine, aromatic amine, amide, and ether oxygen atom provide ad equate water
solubility that allows aripiprazole to dissolve in the aqueous contents of the gastrointestinal (GI) tract. Once dissolved, aripiprazole must pass through the GI mucosal membrane
to enter the blood stream. The dichloro phenyl ring, the alkyl chain, and the hydrocarbon
portion of the bicyclic ring provide adequate lipid solubility to allow for absorption. The tertiary amine is primarily ionized within the GI tract, whereas the aromatic amine is primarily
unionized once it leaves the stomach. Remember that ionization is an equilibrium process
with some fraction of unionized molecules present at all times. According to Le Chatelier’s
principle, as soon as one unionized molecule passes through the GI membrane, the equilibrium resets to provide additional unionized molecules. This same principle also allows ionizable functional groups to penetrate the blood brain barrier and enter the central nervous
system (CNS). The same functional groups that allowed aripiprazole to pass through the
GI mucosal membrane also provide sufficient lipid solubility to allow it to cross the blood
brain barrier and reach its target receptors within the CNS.
4. Aromatic amines are much less basic than primary, secondary, and tertiary aliphatic or
alicyclic amines. The reason for this decreased basicity lies in the fact that an aromatic
amine can donate its lone pair of electrons, through resonance, into the aromatic ring, thus
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 469
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making these electrons less available to bind with a proton. Within the structure of aripiprazole, the nitrogen atom of the aromatic amine is directly adjacent to ortho and meta
chlorine atoms. Chlorine has a higher electronegativity than nitrogen and, through induction, each acts as an electron withdrawing group. This further decreases the availability of
the lone pair of electrons on the nitrogen, resulting in a decrease in basicity. Thus, the pKa
for this particular aromatic amine would be expected to be at the lower end of this range
(i.e., closer to 2).
5. The answer here is No. Tolbutamide and losartan are acidic drug molecules due to the presence of an acidic sulfonylurea and a tetrazole functional group, respectively. Aripiprazole
is a basic drug molecule due to the presence of a tertiary amine and an aromatic amine.
Acidic drug molecules primarily bind to albumin whereas basic drug molecules primarily
bind to α1-glycoprotein. Plasma protein binding interactions (also known as plasma protein displacement interactions) occur due to the nonspecific nature of the plasma proteins
that bind and transport drug molecules. These types of interactions are only therapeutically important when the drug molecules are highly plasma protein bound (i.e., > 90%).
Although this is true of all three drugs, the difference in their acid/base nature significantly
decreases the probability of a drug interaction due to plasma protein displacement.
Shown below are two examples of water-soluble organic salts using lactic acid and citric
6.
acid. There are several other water-soluble organic acids that could be used (e.g., fumaric
acid, malic acid, maleic acid, tartaric acid).
7. There are only two methylene groups that would be expected to generate a chiral center
via metabolism: the benzylic carbon atom and the carbon atom adjacent to the sp2 carbonyl. Oxidation at either of these two positions adds a hydroxyl group and generate a
chiral center. Oxidation of carbon atoms 1 to 5 leads to oxidative N-dealkylation and the
initial formation of an aldehyde. Similarly, oxidation of carbon atom 8 leads to oxidative
O-dealkylation and the initial formation of an aldehyde. Oxidation of methylene groups
in the middle of an alkyl chain and adjacent to an sp3 hybridized center generally does not
occur.
8. One example is shown below. Other binding interactions are possible among these four
functional groups and four amino acids. Isoleucine could form van der Waals and hydrophobic interactions with the halogenated aromatic ring, whereas tyrosine could form the same
470 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
types of interactions with the alkyl chain. Aspartic acid could form an ion–dipole interaction
(as the ion) with the amide, whereas glutamine could form an ion–dipole interaction (as the
dipole) with the ionized tertiary amine. Please note that it is possible for tyrosine to form
hydrogen bonds with the amide and an ion–dipole interaction (as the dipole) with the ionized tertiary amine. However, in the scenario given in this question, if tyrosine were used
to form an interaction with either the amide or the ionized tertiary amine, neither aspartic
acid nor glutamine could be used to form van der Waals and hydrophobic interactions with
the halogenated aromatic ring.
9. Metabolite A: Aromatic oxidation, Phase I
Note: This is somewhat of an unexpected metabolite because the presence of halogen
substituents on the aromatic ring generally deactivates these rings from oxidation. The
difference in this particular drug molecule is the presence of an adjacent aromatic amine.
This aromatic amine can donate electrons into the ring via resonance and either override or
neutralize the electronic effects of the chloro groups, thus allowing for aromatic oxidation.
Metabolite B: Benzylic oxidation, Phase I
Note: Due to the ability to form a conjugated system, this secondary hydroxyl group read-
ily undergoes dehydration to form the following metabolite.
Metabolite C: Oxidative N-dealkylation followed by oxidation of the resulting aldehyde to
a carboxylic acid by aldehyde dehydrogenase, Phase I
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 471
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Cefprozil (Level 1)
1. Functional group names and other information is provided below.
Character:
Acidic,
Basic, or
Character:
Name of
Functional
Group
A Phenol Hydrophilic
B Primary
amine
C Amide Hydrophilic
D Lactam
(cyclic
amide)
E Thioether Hydrophobic Neutral Absorption Hydrophobic
F Carboxylic
acid
G Alkene Hydrophobic Neutral Absorption Hydrophobic
A = H-bond acceptor; Ar = aromatic hydrocarbon; D = H-bond donor; R = carbon skeleton.
a
“None” is a possible answer.
Hydrophilic
and/or
Hydrophobic
(OH)
Hydrophobic
(Ar)
Hydrophilic
(NH2)
Hydrophobic
(R)
(CONH)
Hydrophobic
(R)
Hydrophilic
(CON)
Hydrophobic
(R)
Hydrophilic
(COOH)
Hydrophobic
(R)
Neutral
(Provide
When
pK
a
Relevant)
Acidic
(pK
9-10)
a
Basic
(pKa 9-11)
Neutral Solubility
Neutral Solubility
Acidic
(pK
2.5-5)
a
Function:
↑ Solubility
and/or ↑
Absorption
Solubility
(OH)
Absorption
(Ar)
Solubility
(NH2)
Absorption
(R)
(CONH)
Absorption
(R)
(CON)
Absorption
(R)
Solubility
(COOH)
Absorption
(R)
Function:
Interaction(s) Possible
with Biological Target
at Physiologic pH (7.4)
OH:
H-bonding (A+D)
Dipole-dipole
Ion-dipole (as the
dipole)
Ar:
van der Waals
Hydrophobic
π-π Stacking
Cation-π (as the π
cloud)
Ion-dipole (as the ion)
Ionic
Cation-π (as the cation)
H-bonding (A + D)
Dipole-dipole
Ion-dipole (as the
dipole)
H-bonding (A)
Dipole-dipole
Ion-dipole (as the
dipole)
van der Waals
H-binding (A)
Ion-dipole (as the ion)
Ionic
van der Waals
Function:
Amino Acids
That Can
Interact with
Functional
Group via
H-bonding (at
pH = 7.4)
Ser, Tyr, Trp,
None
Ser, Tyr, Thr,
Ser, Tyr, Thr,
None
None
None
a
His, Thr, Cys,
Asn, Gln,
Met
Cys, Asn,
Gln, Trp, His,
Met
Cys, Asn,
Gln, Trp, His
472 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
2. Cefprozil contains two acidic functional groups (phenol and carboxylic acid) and one basic
functional group (primary amine). Because this drug contains both acidic and basic functional groups, it is considered amphoteric in nature.
3. Functional groups, their acidic or basic nature, the pKa that matches, and the ionization
status at the various pH levels are shown below.
Name of
Functional
Group
Phenol Acidic
Carboxylic
acid
Primary
amine
Acidic or
Basic (pK
=10
pK
a
Acidic
pK
=1.7
a
Basic
pKa=7.2
Ionized or
Unionized
at pH = 5
)
(Saliva)
a
Unionized Unionized Unionized Unionized Unionized
Ionized Unionized Ionized Ionized Ionized
Ionized Ionized Likely
Ionized or
Unionized
at pH = 1
(Stomach)
Ionized or
Unionized
at pH = 7.4
(Plasma)
50%/50%
ionized/
unionized
Ionized or
Unionized
at pH = 8
(Intestine)
Unionized Ionized
Ionized or
Unionized
at pH = 6
(Urine)
4. Drug absorption is enhanced as hydrophobic character is increased. Cefprozil contains several hydrophobic functional groups, including the aromatic ring portion of the phenol, the
thioether and the alkenes. In the stomach (pH = 1) the carboxylic acid and the phenol are
predominantly unionized; however, the primary amine is primarily ionized. In the intestine
(pH = 8) the phenol and the primary amine are unionized and the carboxylic acid is primarily ionized. This means that cefprozil will always be predominantly in an ionized form
regardless of the GI location. A quick reminder: An equilibrium exists between the ionized
form and the unionized form of a drug molecule. In the case of cefprozil only a small fraction of the drug is completely unionized at any point regardless of its location within the
GI tract. When cefprozil is in its unionized form, there is sufficient hydrophobic character
to permit the drug to cross the lipid bilayer membranes of the GI tract and enter systemic
circulation. Based on this evaluation, it is possible that drug absorption can occur in both
GI compartments.
5. As described in Chapter 7, geometric isomers are not mirror images of one another and
are not superimposable. These isomers are a result of the presence of a carbon-carbon
double bond. This double bond causes conformational restriction and forces the double
bond substituents to be positioned in one of two orientations. Either the methyl group and
the bulk of the cefprozil molecule are on opposite sides of the double bond (E geometric
isomer) or they are on the same side of the double bond (Z geometric isomer). Geometric
isomers have different physical and chemical properties. In this example, the geometric
isomers have the same pharmacological action. In general, geometric isomers may have
similar or different pharmacological activities. NOTE: In the case of cefprozil, the E-isomer
is predominant and has much more activity against gram (-) organisms than the Z-isomer.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 473
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6. There are three chiral centers within the structure of cefprozil. Because there is more than
one chiral center, diastereomers are possible. Diasteromeric pairs occur when one chiral
center is held constant (e.g., S-enantiomer) and another chiral center changes stereochemical orientation (e.g., from R-enantiomer to S-enantiomer). In the case of cefprozil, diasteromeric pairs occur when two centers are held constant and the third chiral center changes
stereochemical orientation or when one center is held constant and the other two chiral
centers change stereochemical orientations. Diastereomers are not superimposable (like
enantiomers) and are not mirror images (unlike enantiomers). Diastereomers are expected
to have different physical and chemical properties.
7. The metabolic transformations are listed below.
Name of Transformation Phase I or Phase II
A Oxidative deamination Phase I
B Aromatic hydroxylation Phase I
C Amide hydrolysis Phase I
D Sulfate conjugation Phase II
E Allylic oxidation Phase I
F Amino acid conjugation (with
glycine)
Phase II
8. The hydrolysis of the β-lactam bond by chemical and enzymatic mechanisms is shown
below.
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