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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5323_Библиотеки_им_академика_М_И_Перельмана
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354 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
5. Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of infections caused
by gram-negative pathogens. A series of analogs (A–D) were synthesized in a research laboratory and tested at Abbott Laboratories. The testing results indicated that only analog A
was effective in killing gram-negative pathogens, and the rest were completely inactive.
Provide a structural rationale for why you think that the other analogs were inactive.
6. RAD-1901 is an investigational selective estrogen receptor degrader that acts as an estrogen receptor antagonist in breast and uterine tissues and an estrogen receptor agonist in
bone. Unfortunately, it undergoes rapid metabolism to a series of inactive metabolites.
Propose at least two different isosteric modifications that will limit or prevent this rapid
metabolic inactivation and provide a rationale for how each modification will decrease the
potential for metabolic inactivation.
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 355
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7. Cannabinoid SARs were first reported in the early 1940s. A molecule possesses cannabinoid activity if it includes the following requirements:
y Benzopyran ring (oxygen atom can be replaced by nitrogen atom)
y Nonplanar alicyclic ring (3, 4 position). Planar ring reduces activity. A bulky substituent
at the 4 position is acceptable instead of a nonplanar alicyclic ring.
y Substituents on the alicyclic ring are acceptable without loss of activity.
y The alicyclic ring attachment to the benzopyran ring can be substituted by a heterocy-
clic ring.
y In the aromatic ring, esterification of the phenol is acceptable.
y The length of the aromatic side chain can vary, but a three-carbon chain is minimally
required. Branching of this chain enhances potency. Attachment of the side chain to the
aromatic ring can be via an oxygen atom.
The structure of tetrahydrocannabinol is drawn below. Box each of the structural
A.
requirements and label A–F.
B. Evaluate the structure of the tetrahydrocannabinol analog against the SAR required
for cannabinoid activity. Determine if this analog possesses cannabinoid activity and
provide a brief structural rationale for your answer.
8. The thiazide diuretics bind to Cl– site of the distal tubular Na+/Cl– Cotransporter system and
prevent sodium and chloride reabsorption. Structural modification can lead to enhanced
diuretic effect and/or duration of action. Using the list of structural modifications below,
analyze each pair of thiazide diuretics and answer the questions posed.
y N-2 Substitution decreases polarity and increases duration of action
y Lipophilic groups at C-3 enhance diuretic effect and increase duration of action
356 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
y Saturation of the 3,4-double bond enhances diuretic effect
y An electron withdrawing group at C-6 enhances diuretic effect (e.g., chloro, CF3)
y Unsubstituted C-7 sulfamoyl group (SO2NH2) enhances diuretic effect
Pair #1 (Chlorothiazide and Hydrochlorothiazide): Which drug has the greater diuretic
effect? Provide a brief structural rationale for your answer.
Pair #2 (Chlorothiazide and Benzthiazide): Which drug has a longer duration of action?
Provide a brief structural rationale for your answer.
Pair #3 (Methylclothiazide and Bendroflumethiazide): Which drug has a longer duration of
action? Provide a brief structural rationale for your answer.
9. The fibric acid derivatives stimulate lipoprotein lipase (lowering triglyceride levels) and are
PPARα agonists (increasing high-density lipoprotein levels). The fibrates bind to PPARα via
an ion–dipole interaction with a tyrosine residue within PPARα. Fibrates with a para chloro
substituent or chloro containing substituents have significantly longer half-lives. Evaluate
the following pair of fibric acid derivatives and answer the questions posed.
A. Which drug is able to interact with PPARα? Provide a structural rationale for your
answer. If a drug is unable to interact with PPARα, then determine which Phase I metabolic transformation(s) must occur for the drug to be in its active form and interact
with its biological target?
CH 9 - STRUCTURE ACTIVITY RELATIONSHIPS AND BASIC CONCEPTS IN DRUG DESIGN 357
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B. Which drug has a longer duration of action? Provide a structural rationale for your
answer.
10. In patients diagnosed with pulmonary arterial hypertension (PAH) there is a downregulation of prostacyclin synthetase resulting in less PGI2 production. This vasoactive prostaglandin binds to and activates the IP receptors leading to important vasodilation and
antiproliferative activity. PGI2 (aka epoprostenol) and two synthetic PGI2 analogs that are
used in the management of PAH are drawn below.
Evaluate each drug molecule and each SAR in the table. Place a check mark or comment in
the table if the drug molecule follows the SAR.
Epoprostenol (PGI2) Ilprost 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)
358 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
11. Dasatinib is tyrosine kinase inhibitor that is used to treat Philadelphia chromosome-
positive (Ph+) acute lymphoblastic leukemia (ALL) in both adults and pediatric patients
older than 1 year. The structures of dasatinib and two isosteres of dasatinib are shown
below. The isosteric changes are boxed.
A. For Isostere A, indicate if this is a classical or a nonclassical isostere and predict how
this isosteric change could alter the ability of dasatinib to bind to its target receptor.
B. For Isostere B, indicate if this is a classical or a nonclassical isostere and predict how
this isosteric change could alter the duration of action of dasatinib.
12. As a pharmacy student, your medicinal chemistry processor constantly uses the abbreviation “SAR” in his class.
A. Explain what these initials represent and what this term means.
B. What is the most important component of an SAR?
WHOLE MOLECULE
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10
DRUG EVALUATION
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Evaluate a drug structure and identify the key structural features required to address a
specific structure-based question.
• Identify the appropriate concepts applicable to answering specific structure-based
questions.
• Correctly apply basic medicinal chemistry concepts to drug- and structure-based
questions.
The Structural Analysis Checkpoint questions in Chapters 2 to 9 allowed you to sequentially answer
questions pertaining to venetoclax and elamipretide as new concepts were introduced. By the end
of Chapter 9, whole molecule drug evaluations had been conducted for these two drugs. In this final
chapter, twelve additional drugs, drug pairs, or drug classes have been selected for similar whole
molecule drug evaluation. Unlike the previous chapters, in which the questions focused specifically
on one or two concepts, the questions here challenge you to conduct a comprehensive evaluation
of the selected drugs and select the concepts that are applicable to the scenarios provided.
The selected examples represent three levels of evaluation.
Level 1: evaluates the chemical properties of a single drug molecule.
1.
2. Level 2: evaluates a pair of structurally related drugs and requires the reader to compare
and contrast their chemical properties.
3. Level 3: evaluates multiple drugs within a single chemical/pharmacological class and
requires an evaluation of the structure activity relationships (SARs) of the drug class.
The answers to all of these questions can be found in the Appendix.
ALISKIREN (LEVEL 1)
Aliskiren is an orally active agent used in the treatment of hypertension. This nonpeptide drug
acts as an inhibitor of renin, the enzyme that converts angiotensinogen (its endogenous substrate) to angiotensin I. Biologically inactive, angiotensin I is rapidly converted to angiotensin II
DOI 10.37573/9781585286959.0 10
359
360 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
by angiotensin-converting enzyme. Angiotensin II is a potent agonist when bound to its receptor
and produces significant vasoconstriction as well as an increase in blood pressure. In the presence
of aliskiren, angiotensinogen is not converted to angiotensin I, so less angiotensin II is produced to
activate the angiotensin II receptor. Consequently, less vasoconstriction occurs, and a drop in blood
pressure results.
1. Conduct a structural evaluation of aliskiren, focusing on the boxed functional groups, and
use the information in the grid to inform your answers to the questions that follow.
Function:
Amino Acids
Character:
Name of
Functional
Group
A
B
C
D
E
F
a
“None” is a possible answer.
Hydrophilic
and/or
Hydrophobic
Character:
Acidic, Basic,
or Neutral
(Provide
pKa When
Relevant)
Function:
Contribute
to Aqueous
Solubility and/
or Contribute to
Absorption
Function:
Interaction(s)
Possible with
Biological
Target at
Physiologic
pH = 7.4
That Can
Interact with
the Functional
Group via
Ion–Dipole
Interactions at
pH = 7.4
a
2. Aliskiren is marketed as the pure 2S, 4S, 5S, 7S enantiomer. Circle all of the chiral carbon
atoms and determine if diastereomeric or geometric isomers are possible.
3. Although aliskiren is administered orally, its oral bioavailability is ∼2.5% and is very poorly
absorbed. Using the information in the structure evaluation grid, provide a structural
rational for this unfortunate property.
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It
is unknown how much of an absorbed dose is metabolized, and several metabolites from
CH 10 - WHOLE MOLECULE DRUG EVALUATION 361
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CYP3A4 mediated transformations have been identified. Several possible metabolic products are drawn below. Identify which metabolic transformation has occurred and whether
it represents an oxidative transformation.
362 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Name of Metabolic Transformation Oxidative or Nonoxidative
A
B
C
D
E
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure of
angiotensinogen. The structure of aliskiren contains functional groups that mimic the side
chains for these two amino acids. The hydrolyzable peptide bond (found between LeuVal) has been replaced by a nonhydrolyzable hydroxyethylene group in aliskiren. Circle the
functional groups that mimic the amino acid side chains of these two amino acids and box
the nonhydrolyzable hydroxyethylene group.
6. Aliskiren can be coadministered with other antihypertensive agents to provide better
hypertension management. Amlodipine is a second-generation dihydropyridine calcium
channel blocker used in the treatment of hypertension. Aliskiren and amlodipine are both
plasma protein bound (47% to 51% and 93% to 97%, respectively). How likely is it that a
plasma protein binding interaction will occur if these drugs are coadministered?
ARIPIPRAZOLE (LEVEL 1)
Shown below is the structure of aripiprazole, a serotonin receptor modulator used for the treatment
of depression, schizophrenia, autism, mania, and bipolar disorder.
CH 10 - WHOLE MOLECULE DRUG EVALUATION 363
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1. Identify all of the acidic and basic functional groups, provide the normal pKa range for each
of the identified functional groups, and identify if each functional group would be primarily
ionized or unionized at a urine pH of 5.6.
2. Identify all of the remaining functional groups and indicate how each group contributes to
the overall water solubility or the overall lipid solubility of aripiprazole.
3. Using your answers from the previous two questions, provide an explanation as to why
aripiprazole can be administered orally for the indications previously listed.
4. The acidity and basicity of functional groups can vary based on the presence or absence of
adjacent functional groups. The normal pKa range for an aromatic amine is 2 to 5. Conduct
a structural evaluation of aripiprazole and predict whether the pKa of the aromatic amine
present would be expected to be at the lower or upper end of this range. Provide a rationale
for your prediction.
Drug molecules that are highly plasma protein bound may undergo a drug interaction due
5.
to the displacement of one drug molecule from a plasma protein by another drug molecule. Shown below are the structures of tolbutamide and losartan. Both of these drugs
are highly plasma protein bound. Aripiprazole is also highly plasma protein bound (> 99%).
Would you expect there to be a drug interaction between aripiprazole and either tolbutamide or losartan?
6. Draw a water-soluble organic salt of aripiprazole.
7. The structure of aripiprazole does not contain any chiral carbon atoms and thus does not
have enantiomers. Its structure contains 10 prochiral methylene (CH2) groups that could
potentially be converted to chiral centers. Using the known metabolic pathways discussed
in Chapter 8, identify which of these 10 prochiral methylene atoms are most likely to generate a chiral center on metabolism.
8. Assume that the boxed functional groups of aripiprazole form four key binding interactions
with a serotonin receptor. Further assume that these binding interactions occur with the
side chains of Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between aripiprazole and the given amino acids. Assume that this binding
interaction occurs at a physiologic pH of 7.4.
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