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344 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
interferon alfa-2a and alfa-2b. The general structure of monomethoxy PEG is shown below. It can
be linked to proteins in a linear fashion or as a single branch with lysine.
Isavuconazole is an azole antifungal drug indicated for the treatment of invasive aspergillosis
and invasive mucormycosis in adults. Similar to other azole antifungals, it exerts its mechanism of
action by inhibiting the fungal synthesis of ergosterol. It is marketed as an N-(3-acetoxypropyl)-
N-methylamino-carboxymethyl prodrug known as isavuconazonium sulfate (Figure 9-30). The
prodrug is highly water soluble and can be given either orally or via IV injection. The enhanced water
solubility allows it to be formulated without a cyclodextrin vehicle, thus avoiding the concerns of
nephrotoxicity seen with other parenteral azole antifungals (e.g., posaconazole and voriconazole).
As shown in Figure 9-29, hydrolysis of the carbamate releases an unstable carbinolamine that spontaneously degrades to generate isavuconazole.
FIGURE 9-30.The bioactivation of isavuconazolium to isavuconazole.
Brentuximab vedotin (Figure 9-31) is an antibody-drug conjugate directed against the CD30
antigen expressed in Hodgkin lymphoma and anaplastic large cell lymphoma. The antibody, brentuximab, is linked to a cytotoxic drug, monomethylauristatin E (MMAE), via a valine-citrulline dipeptide and a para-aminobenzylcarbamate spacer. This linker ensures that the cytotoxic MMAE is not
easily released from the antibody under physiologic conditions, thus helping to prevent toxicity to
noncancerous cells. The antibody binds to CD30 found on the surface of malignant cells (such as
Hodgkin’s lymphoma cells) and the conjugate is internalized. Once this conjugate enters the lysosomal compartment, the acidic environment allows cathespin B to cleave the linker and release MMAE.
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FIGURE 9-31.Brentuximab vedotin (mAb = brentuximab).
Mechlorethamine (Figure 9-32) is an alkylating agent used in the treatment of a variety of neoplastic disorders including Hodgkin’s disease and chronic lymphocytic leukemia. Mechlorethamine
is highly reactive with a half-life of less than 10 minutes. It is available as a powder that must be
dissolved in either sterile water or normal saline immediately prior to use. Due to its high reactivity,
mechlorethamine must be administered as an IV bolus injection over 2 to 5 minutes, and extreme
precaution must be taken with its administration. Similar to mechlorethamine, the structure of
cyclophosphamide contains two β-chloro ethyl groups that are required for alkylation. The primary
FIGURE 9-32.The mechanism of alkylation of mechlorethamine and the bioactivation of
cyclophosphamide (a prodrug analog of mechlorethamine).
346 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
difference between these two drugs is that cyclophosphamide is an inactive prodrug. The presence of
the unionized phosphoramide withdraws electrons from the adjacent nitrogen atom, thus preventing
it from attacking the β-chloro ethyl groups. As such, it does not possess the high reactivity observed
with mechlorethamine and has a much longer half-life (8 hours). It can be administered orally and
as either an IV bolus injection or as a slow IV infusion. Similar to mechlorethamine, cyclophosphamide must be dissolved in sterile water, normal saline, or 5% dextrose solution; however, these
solutions are stable for up to 24 hours. Once administered, it undergoes oxidative N-dealkylation.
The resulting intermediate is unstable, and the subsequent reaction releases the active metabolite
of cyclophosphamide. This active metabolite contains an ionized phosphate amide that alters the
electronics of the functional group and allows it to form the same reactive aziridinium ion as seen
with mechlorethamine. Due to its prodrug nature, cyclophosphamide is a safer agent and is much
easier to administer. This has led to its preferential use and approval for the treatment of a wide
variety of neoplastic disorders (i.e., cancers).
Throughout this text, NSAIDs have been discussed and used as examples. Most drugs in this
class nonselectively inhibit cyclooxygenase enzymes, COX-1 and COX-2, and as a result decrease
the biosynthesis of prostaglandins. Although this action is beneficial in providing analgesic, antiinflammatory, and antipyretic effects, it can also lead to GI distress, including ulceration and bleeding. There are two reasons for these adverse effects. First, NSAIDs must contain an acidic functional
group to interact with cyclooxygenase enzymes (see discussion in Chapter 2). Unfortunately, acidic
functional groups represent a primary insult to the GI system and can directly cause irritation, ulceration, and bleeding in some patients. Second, due to their nonselective nature, most NSAIDs inhibit
the GI production of PGE
and PGI2. These prostaglandins are responsible for inhibiting gastric acid
2
secretion, increasing mucus secretion, helping to maintain the integrity of the gastric mucosa, and
inhibiting gastric damage caused by ulcerogenic compounds. The use of a nonacidic prodrug, such
as nabumetone (Figure 9-33), eliminates the direct GI effects caused by active, acidic NSAIDs.
Additionally, because the prodrug is not active until it is absorbed and undergoes bioactivation,
there is not as much local inhibition of PGE2 and PGI2 biosynthesis.
FIGURE 9-33.The bioactivation of nabumetone to its active metabolite.
Methenamine and omeprazole are examples of prodrugs that are selectively activated at their
sites of action. Formaldehyde (CH2O) has been shown to be effective in treating urinary tract infections due to its ability to denature bacterial proteins. The actions of formaldehyde are not specific for microorganisms, so direct administration of formaldehyde, either orally or parenterally,
would cause significant toxicity to a patient. To circumvent this problem, the prodrug methenamine was developed. As shown in Figure 9-34, methenamine undergoes bioactivation to produce
FIGURE 9-34.The bioactivation of methenamine to formaldehyde.
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formaldehyde in an acidic environment. To avoid degradation in the stomach, methenamine is
administered as an enteric-coated tablet, which prevents its release until it reaches the small intestine, where it undergoes dissolution and absorption. At a physiologic pH of 7.4, methenamine is stable and does not release formaldehyde in the blood or other tissues; however, once methenamine
is filtered or secreted into the urine, the normal acidic environment (pH ∼5-6) of the urine releases
formaldehyde. Once this occurs, formaldehyde can exert its effects on the microorganisms that are
responsible for causing the urinary tract infection.
Omeprazole (Figure 9-35) is a proton pump inhibitor used in the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease, and other hypersecretory conditions. The proton
pump, also known as H+/K+-ATPase, is a transport protein located in the parietal cells of the gastric
mucosa that is responsible for secreting protons into the stomach (i.e., acid secretion). Omeprazole
and other drugs within this chemical/pharmacological class of drugs irreversibly inhibit this process by covalently binding to H+/K+-ATPase. Because covalent bond formation requires the drug
to be highly reactive, omeprazole and other drugs within this class were designed as site selective
prodrugs. The acid catalyzed rearrangement illustrated in Figure 9-35 can occur only in the highly
acidic environments found in the stomach and the parietal cells. Similar to methenamine, the use of
an enteric-coated formulation allows omeprazole to be released and absorbed in the small intestine.
Once it reaches the parietal cells, the acid catalyzed rearrangement occurs and the reactive interme-
+/K+
diate is formed in very close proximity to H
-ATPase. A cysteine residue present on H+/K+-ATPase
readily reacts with the active metabolite to irreversibly inhibit the transport protein.
FIGURE 9-35.Bioactivation of omeprazole and the reaction of the active metabolite with
H+/K+-ATPase.
348 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
SUMMARY
Structure activity relationships represent a cornerstone for the discipline of medicinal chemistry as
they define the chemical rationale for a given physicochemical, pharmacological, and/or therapeutic response. The electronic, physicochemical, and steric contributions of functional groups present
within the structure of a drug molecule affect the drug molecule’s ability to interact with specific
biological targets and produce specific pharmacological effects. Additionally, functional groups and
the overall structure of a drug molecule determine the absorption, distribution, metabolism, and
excretion of the drug. Finally, certain drug interactions and adverse drug reactions can be directly
linked to a specific functional group or structural feature within a drug molecule. As you progress
to the study of specific drug molecules and drug classes, remember that each SAR statement that
you encounter should include a “why” or “how” component that links a specific functional group
that is inherent within the chemical structure to a specific physicochemical, pharmacological, or
therapeutic effect.
Molecular modification of a lead compound is a commonly used strategy to develop new drug
molecules. This strategy has been successful in enhancing the potency and/or selectivity of a lead
compound, altering the water/lipid solubility balance to meet a specific need, optimizing the duration of action, and decreasing drug interactions and adverse drug reactions. Conformational restriction, the variation of functional groups, the use of isosteres, homologation, chain branching, and
the conversion of an active drug molecule to a prodrug are the most common types of molecular
modification. Reviewing these strategies can help you to understand the rational design of drug
analogs and how the SARs for a specific class of compounds were established. Additionally, because
these types of modification are common, you are likely to encounter them in the future whenever
new drugs are approved by the FDA.
STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
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1. For the purpose of this question, assume that a research group designed six analogs of
venetoclax by replacing the boxed para chloro group with the following functional groups:
F, OH, NO2, OCH3, CH3, and CN. In testing these compounds and comparing their activities
to venetoclax, it was found that the F group retained activity, the NO2 and CN analogs had
enhanced activity, the CH3 analog was 100 times less active, and the OH and OCH3 analogs
were essentially inactive. What SAR can be deduced from this information?
2. For the purpose of this question, assume that a research group designed four analogs of
venetoclax by replacing the boxed pyrrolopyridine bicyclic ring with the following four rings.
In testing these analogs and comparing their activities to venetoclax, it was found that
Analog B had similar activity, Analog D was 10 times less active, and Analogs A and C were
1,000 times less active. What SAR can be deduced from this information?
3. The boxed ether oxygen can be isosterically replaced by a secondary amine (-NH-) or a
methylene carbon atom (-CH2-). For each of these isosteric replacements, explain how
their chemical differences could affect the actions of venetoclax.
4. Evaluate the structure of venetoclax and determine if it could easily be converted to a
prodrug to enhance water solubility.
Checkpoint Drug 2: Elamipretide
Elamipretide is part of a family of tetrapeptides called the Szeto-Schiller (SS) peptides. It was discovered when a library of small molecules was screened for µ-opioid receptor activity. The ability
of this agent to restore bioenergetics in aging and in a variety of disease states was a serendipitous
discovery.*
A. SS-02 was found to have potent central analgesic activity (µ agonist). It is taken up
by several cell types without the need for transporters or receptors. It crosses lipophilic membranes (including the blood brain barrier) without the need for transporters.
SS-02 selectively partitions into the inner mitochondrial membrane.
SS-31 (elamipretide) and SS-20 also selectively partition into the inner mitochondrial
B.
membrane but do not possess µ agonist activity.
C. Only SS-31 and SS-20 bind to cardiolipin, which is expressed in the inner mitochondrial
membrane.
D. An electrostatic interaction occurs between the two basic amino acids found in the
tetrapeptides and the phosphate head found within cardiolipin. This causes alignment
of the hydrophobic amino acids/amino acid derivatives with a hydrophobic region
within cardiolipin.
*Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochon-
drial plasticity. Clin Pharmacol Ther. 2014;96(6):672-683.
350 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
1. Evaluate the amino and carboxy terminal amino acids for each of the three tetrapeptides
and list the possible binding interactions in the table provided. Which interactions are
unique to SS-02 that might be required for µ receptor activation?
Amino Terminus Carboxy Terminus
SS-31 (elamipretide)
SS-02
SS-20
2. Consider the spatial positioning of the two basic amino acids found within each of these
tetrapeptides. Given the need to participate in electrostatic interactions with a phosphate
head, provide a rationale for why all three peptides should be able to participate in this type
of interaction.
3. Consider the locations of the hydrophobic amino acids relative to the two basic amino
acids found within each of these tetrapeptides. Provide a rationale for why only SS-31 and
SS-20 bind to cardiolipin.
4. In Chapter 8 you evaluated a prodrug form of elamipretide (drawn below).
A. List two reasons why delivery of a prodrug might be valuable.
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B. Provide a structural rationale for why this prodrug is not degraded by amino- and
carboxypeptidases.
REVIEW QUESTIONS
1. Endogenous insulin is a polypeptide composed of two peptide chains (A and B chain). The A
chain is 21 amino acids long and the B chain is 30 amino acids long. The two peptide chains
are linked by two critical disulfide bonds. A portion of the A chain is cyclic due to the presence of an additional disulfide bond. For insulin to exert its action, it must interact with and
activate insulin receptors that are located on target cells. The SARs associated with this
endogenous hormone are listed below.
Insulin A chain SAR:
1. Shorten chain ∴ virtually no biological activity (lifts termini of A chain off receptor
surface)
2. Remove C-terminal asparagine ∴ no biological activity (key receptor binding
interaction)
3. Replace N-terminal glycine with -alanine ∴ retain biological activity (steric require-
ment allows addition of small hydrophobic substituent)
4. Replace N-terminal glycine with -alanine ∴ no biological activity (tight steric require-
ments on receptor binding surface)
5. Remove N-terminal glycine ∴ no biological activity (key receptor binding interaction)
Insulin B chain SAR:
1. Remove first 6 amino acids from N-terminus ∴ retain biological activity (no interfer-
ence with key receptor binding interactions)
2. Remove last 3 amino acids from C-terminus ∴ retain biological activity (no interfer-
ence with key receptor binding interactions)
3. Single residue d eletions B24 to B26 provide analogs twice as potent as insulin (improved
receptor binding interactions)
352 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
General Insulin A and B chain SAR:
1. Amino acids can be replaced inside the chains; be careful how many are (D) (alter conformation of protein when there are too many D amino acids)
2. Disulfide linkages (3) must be present for biological activity (required for active conformation of hormone)
The primary structure of insulin is highly conserved across several animal species. A geneti-
cist recently isolated and characterized several forms of insulin from the Catywhompus, a
rain forest dwelling animal. He identified several molecular characteristics found within
the insulin mimics and tried to predict whether any of these insulins would be biologically active in humans. Consider the SAR requirements for insulin provided and each set of
structural characteristics and determine if the insulin is likely to be ACTIVE or INACTIVE in
humans. If the insulin is INACTIVE, then indicate which structural feature(s) is/are likely to
be the problem.
A. Insulin #1: Several amino acids are different from those found in human insulin in the A
chain. Overall, the number of amino acids in the A chain remains the same. The amino
and carboxy terminal residues remain identical to that of human insulin. One disulfide
bond is present. Otherwise, the insulin structure is identical to human insulin.
B. Insulin #2: The primary structure of the B chain is nearly identical to that of human
insulin; however, it is shorter at the amino terminus by 10 amino acids and at the carboxy terminus by 2 amino acids. Otherwise, the insulin structure is identical to human
insulin.
C. Insulin #3: Almost half of the amino acid residues in both the A and B chains are
-amino acids. A total of three disulfide bonds are present in the insulin molecule. The
A chain amino terminus has been replaced by -alanine. Otherwise, the insulin struc-
ture is identical to human insulin.
2. The sulfonylurea (e.g., glipizide) and meglitinide (e.g., repaglinide) classes of antidiabetic
agents are effective in the treatment of type 2 diabetes because of their ability to increase
insulin secretion from the pancreatic β cells. An acidic functional group is a structural
requirement for activity. The meglitinide class of agents is derived from the sulfonylureas.
Which type of molecular modification has occurred in this evolution?
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3. There are several insulin analogs currently marketed that have a shorter onset and duration
of action as compared with the endogenous hormone (see partial structures below). The
insulin in these formulations is inactive and must undergo at least one dissociation step
after administration to the active monomer.
From a structural perspective these insulin analogs have been altered at the B chain
C-terminus, an area of the peptide that is not involved in receptor binding interactions.
In Humulin R, the proline residue (position 28) causes a conformational kink in the protein structure and a “hook” is formed. There is some evidence that this “hook” allows for
insulin-insulin dimerization. In Humulin R, the insulin dimers must dissociate to the active
monomer, a process that takes a small amount of time. Humulin R is considered a shortacting insulin.
Provide a structural rationale for why Lispro and Insulin Aspart are considered ultra-short
insulins. Be sure to include in your answer a discussion about dimer formation.
4. Tazarotene is marketed as a prodrug for the topical treatment of psoriasis, acne, and sun
damaged skin. Activation of the drug is shown below. Provide a potential rationale for why
tazarotene is modified to be an ester. (HINT: Agents that are administered topically must
absorb into the hydrophobic components of the skin to be effective. Remember, absorption across lipophilic membranes is improved as hydrophobic character increases.)
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