Solutions To End-of-Chapter Questions: Erland Stevens Medicinal Chemistry and Drug Discovery - Solutions 1

Erland Stevens
Medicinal Chemistry and Drug Discovery Solutions
Solutions to End-of-Chapter Questions

Chapter 2
Question 1
Approving raloxifene for a second use would very likely require less than 7-8 years. The safety data
for the original Phase I trials (osteoporosis) would not need to be repeated. Since Phase II trails
involve affected (diseased) patients, a new round of Phase II trails for the breast cancer treatment
would be unavoidable. The same would be true for all Phase III trials.
Question 2
Extensive liver damage: This problem would likely be discovered in pre-clinical (animal) trials.
Insufficient efficacy: For most drugs, efficacy is confirmed in Phase II trials.
Causes arthritis after several years with chronic use: Even Phase III trials normally run a few
years at the longest, so very long term problems likely would not be found until some years
after the drug had been launched.
Interacts with certain cardiovascular drugs: Drug-drug interactions are normally uncovered
during Phase III trials.
Question 3
For this problem it is helpful to determine the cumulative costs for each stage of development before
answering the separate questions. So, here are the development costs up to and including different
stages of a drug candidates advancement. The numbers are based on a total cost of US$800 million
and the percentages in Figure 2.16.
Pre-clinical (26%)
$208 million
Phase I (33%)
$264 million
Phase II (43%)
Phase III (69%)
$552 million
Market (100%)
$800 million
$344 million
At this point, just add up the numbers. There are five compounds total. One compound dies in Phase I
($264 million), two compounds die in Phase II ($344 million 2), one compound dies in Phase III
($552 million), and one compound reaches the market ($800 million). Those numbers give a grand
total of approximately $2.3 billion as the development costs for the five compounds.
Question 4
This question builds off the previous one, so most of the work is already done. A blockbuster drug
with 12 years of sales will bring in US$12 billion in sales, and therefore $2.4 billion in profit. A
compound that only advances to Phase I costs $264 million, so a blockbuster can cover the losses
incurred by approximately 9 Phase I busts. Since the blockbuster cost $800 million to develop, its true
profit would be closer to $1.6 billion enough profit to cover 6 compounds that failed in Phase I.
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Similarly, compounds that advance to Phase III cost $552 million. A blockbuster drug with $2.4
billion in profit can offset between 4 and 5 Phase III failures. Accounting for the costs of the
blockbuster drug allows only about 3 Phase III failures to be covered.
Question 5
True category creators can be hard to conceive because they are, by definition, innovative. Innovation
requires one to know something about the existing pharmaceutical market and deficiencies in available
products.
One example of a category creator is orally-available insulin. Insulin taken in a pill form would
immediately become the preferred method for diabetics to receive insulin. Note that patients can get
insulin now, but the method of administration is less than satisfactory.
Other conditions that are currently manageable to some degree but not to a satisfactory level for some
or advanced patients include asthma, Alzheimers disease, depression, multiple sclerosis, Crohns
disease, Parkinsons disease, and many types of addictive behavior.
Chapter 3
Question 1
As it is eliminated, methotrexate (3.45) concentrates in the urine and can precipitate out of solution.
Methotrexate contains two carboxylic acids. If the pH of the blood, and subsequently the urine, is
drops to low, then a larger fraction of the acid groups in methotrexate will be protonated, and the
molecule will be neutralized. The neutral form of methotrexate is less soluble and at risk for
precipitating from solution. Raising the pH of the urine with bicarbonate shifts the equilibrium toward
the deprotonated form(s) of the drug. Deprotonation places negative charges on the structure,
increases water solubility, and minimizes the chance of drug precipitation in the urine.
O
NH2
N
H2N
Me
CO2H
N
H
CO2H
N
methotrexate
3.45
Question 2
Remember that plasma is the non-cellular fraction of whole blood. With a blood-to-plasma ratio of
less than 1 (0.86), alfentanil has a lower concentration in whole blood than plasma. When the cells in
whole blood are opened and their contents mix with the plasma, the drug concentration drops from a
relative value to 1.0 to 0.86. This process is shown below.
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relative intracellular drug concentration = ??
lyse cells and

mix released
cytosol and
plasma
relative whole blood drug concentration = 0.86
relative plasma drug concentration = 1.00
Based upon Figure 3.15, cells constitute 46% of whole blood by volume, and plasma makes up 54% of
the volume of blood. This is all the necessary information to solve what amounts to a M1V1 = M2V2
dilution problem in a general chemistry class. A key point is to remember that the amount of drug in
the volume is constant whether it is divided between the cells and plasma or mixed uniformly within
entire sample volume.
amount drug in plasma cells amount of drug in whole blood
One can determine the amount of drug in a volume by the product of the drugs concentration (C) and
its volume of occupancy (V). For this problem, all variables are known except Ccells, the concentration
of the drug within the cells.
C plasmaVplasma C cellsVcells C bloodVblood
1.00 0.54 C cells 0.46 0.86 1.00
0.46 C cells 0.32
C cells
0.32
0.70
0.46
The relative concentration of alfentanil within the cells of blood to plasma is 0.70.
Question 3
Drugs enter cells of the blood the same way that drugs enter other cells of the body primarily through
passive diffusion. Epoetin alpha is a massive drug with a MW of 18,000. Molecules of this size do
diffuse across the membrane. Epoetin alpha would therefore not be expected to enter the cells of the
blood. Since the cellular concentration of epotein alpha should be near 0, the blood-to-plasma ratio of
epoetin alpha should be less than 1, likely close to 0.5.
Question 4
Figure 3.1 lists the amount of water in the body as 60% of total body mass. For a 70-kg person, that
works out to 42 kg. That 60% is split among oxygen and hydrogen based upon the respective mass
and number of the atoms in water.
% body mass of oxygen from water 60%
16
53.3% (37.3 kg)
18
Erland Stevens
% body mass of hydrogen from water 60%
2
6.7% (4.7 kg)
18
If the calculated masses of oxygen and hydrogen from water are removed from the masses in Table 3.1,
then the remaining masses can be used to calculate the water-free mass percentages for oxygen,
carbon, hydrogen, and nitrogen. The other elements in the body must be kept in the calculation in
some form (even just in an other category) so that the final percentages work out properly.
O, C, H, and N content of a 70-kg person
Iincluding Water
element
mass (kg)
Water
Excluding Water
mass (kg)
mass (kg)
37.3
5.7
20.4
16
57.1
2.3
8.2
Oxygen (O)
43
61.4
Carbon (C)
16
22.9
Hydrogen
(H)
7.0
10.0
Nitrogen (N)
1.8
2.6
1.8
6.4
Others
2.2
3.1
2.2
7.9
total
70
100.0
28
100.0
4.7
42
When water is excluded, carbon is the most predominant element in the body as one might expect from
an organism that consists largely of fats, carbohydrates, and proteins.
Question 5
The mass balance of the cited study is 84.8% and calculated by adding all the listed percentages. The
drug in question would appear to be well absorbed. Any drug found in the urine (65.9%) and tissues
(8.8%) must have been absorbed, so the minimal absorption percentage must be nearly 75%.
Absorption of 75% is a reasonably good value for a drug. Furthermore, the amount of drug found in
the cage rise (4.9%) could be from any number of elimination pathways such as hair, sweat, or saliva.
For a drug to be eliminated through any of these pathways, it must first be absorbed. The absorption of
the drug is therefore likely nearly 80%.
The drug found in the feces (5.5%) may have been absorbed and the excreted in the bile or simply
passed through the rat. Detection of an unchanged drug in the feces is typically a sign that the drug
was never absorbed.
Question 6
Polar surface area is indeed raised by the presence of oxygen and nitrogen atoms (the common
hydrogen bond acceptors) and O-H and N-H bonds (the common hydrogen bond donors). In addition
to hydrogen bond donors and acceptors, polar surface area includes all polarized bonds, including
carbon-halogen bonds. Perhaps surprisingly, carbon-carbon -bonds can be very highly polarized if
they bear strong enough electron-donating and/or electron-withdrawing groups.
Question 7
The kidneys filter waste from the blood that passes through the kidneys. Proteins in the blood are too
large to pass through the initial filter in the glomulerus and therefore are not generally removed by
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kidneys or observed in urine. The presence of protein in the urine is associated with a number of
physiological conditions including various kidney diseases, dehydration, and even very vigorous
exercise.
Question 8
Here is how the three compound stack up to the Lipinskis Rules for CNS drugs in Table 3.11.
Donezepil
MW
H-bond donors
H-bond acceptors
379 g/mol
0
4 (one for each oxygen and nitrogen)
Galantamine
MW
H-bond donors
H-bond acceptors
287 g/mol
1 (alcohol)
4 (one for each oxygen and nitrogen)
Rivastigmine
MW
H-bond donors
H-bond acceptors
250 g/mol
0
2 (one for each oxygen and nitrogen, excluding the amide nitrogen)
All three Alzheimers drugs are (not surprisingly) within the specifications of Lipinski. Some common
software packages, including more recent versions of ChemDraw, can provide clog P values. The clog
P values for the three compounds are 4.01, 1.41, and 2.36, also all in the expected ranges for CNS
drugs.
Compounds that violate Lipinskis Rules for CNS drugs are expected not to diffuse passively across
the blood-brain barrier. Therefore, if a drug has non-ideal properties but still crosses into the brain,
then the compound likely hitches a ride into the CNS through a facilitated or active transport process.
Lipinskis Rules only predict passive diffusion.
Question 9
The upper portions of the small intestine are neutral to slightly alkaline. This environment is idea for
many oral drugs, which often contain weakly basic amines. Under these conditions, a reasonable
fraction of the amines are present in their neutral, basic form and more readily enter into lipophilic
membranes for absorption from the intestinal lumen. A neutral-to-acidic environment such as the
rectum is more ideally suited for weakly acidic drugs. Under weakly acidic conditions, weak acids
tend to be present in their neutral, acid form for improved absorption.
In the small intestine with its higher pH, acidic drugs (drugs containing acidic functional groups such
as carboxylic acids) will be deprotonated to a greater degree than in the rectum.
Question 10
With a density near 1 g/mL, a 70-kg patient has a volume of approximately 70 L. According to Table
3.1, the amount of iron in the body is only 4.2 g, corresponding to 0.075 mol (Fe MW = 55.85 g/mol).
Therefore, the concentration of iron in the body is approximately 1.110-3 M (0.075 mol/70 L), or 1.1
mM. On a purely mass basis, the concentration of iron in the body is approximately 60 ppm
(1,000,000 4.2 g / 70,000 g).
Erland Stevens
The body contains only 15 mg (0.015 g) of selenium (MW 78.96 g/mol), which is just 1.910-4 mol for
a concentration of 2.710-6 M, or 2.7 M. On a mass basis, selenium is present in the body at a
concentration of only 0.21 ppm.
Chapter 4
Question 1
Scheme 4.7 is shown below.
k1
k2
E + S
ES
E + P
k -1
First step, forward reaction:

rate of formation of ES k1 [E ][S]
k1
1
conc time
First step, reverse reaction:

rate of formation of S k 1 [ ES]
k1
1
time
Second step, forward reaction:

rate of formation of P k 1 [ ES]
k1
1
time
Units of Km:
Km
k 2 k 1
k1
(4.12)
1
1
1
1
time
K m time time
1 conc
1
1
1
conc time
conc time conc
Question 2
The key to this question is to remember the impact of each inhibitor upon an enzyme. A competitive,
reversible inhibitor decreases Km without affecting Vmax of an enzyme-substrate combination. The
inhibited and uninhibited reach the same Vmax, but the inhibited system requires a higher [S] to get
there.
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A pure non-competitive, reversible inhibitor does the opposite Km stays constant while Vmax
decreases. Both systems reach Vmax at the same [S].
An uncompetitive, reversible inhibitor decreases both Km and Vmax by the same factor. That is, if the
inhibitor decreases the Km by half, then Vmax likewise decreases by half. The graph below is not
extended to high [S] values so that the key [S] region near Km is clearer.
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Question 3
This question is just an algebraic exercise on the Michaelis-Menten equation. For the first part, replace
V with 0.1Vmax and solve for [S]. To reach 0.1Vmax, [S] must be equal to 1/9 of Km (or 0.11Km).
V
Vmax [S]
K m [S]
0.1Vmax
0. 1
(4.11)
Vmax [S]
K m [S]
[S]
K m [S]
0.1K m 0.1[S] [S]

0.1K m 0.9[S]
1
K m [S]
9
For the second part, replace V with 0.95Vmax and solve for [S]. To reach 0.95Vmax, [S] must be equal to
19Km.
0.95Vmax
0.95
Vmax [S]
K m [S]
[S]
K m [S]
0.95 K m 0.95[S] [S]

0.95 K m 0.05[S]
19 K m [S]
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Question 4
The Lineweaver-Burk equation is given below.
K
1
1
1
m
V Vmax [S] Vmax
(4.13)
This equation has an x-intercept of 1/Km and a y-intercept of 1/Vmax. Based on these two points, the
slope of the line can be calculated.
slope
rise y y1 y 2
run x x1 x 2
Vmax
V
K
max m
1
1
Vmax
0
Km
Km
Question 5
As a competitive inhibitor of fumarase, compound 4.c binds in the active site of the enzyme.
Structurally 4.c resembles both the substrate (fumaric acid, 4.a) and the product ((S)-malic acid, 4.b).
If all three compounds are viewed along side each other in a series of Newman projections, the
overlapping of key functional groups is apparent in two ways. First, aziridine 4.c nearly preserves the
trans orientation of the carboxylic acids in both 4.a and 4.b. Second, the NH in the aziridine ring
matches the position of the OH in (S)-malic acid when the acid groups are held in a trans orientation.
Compound 4.c resembles both the product and substrate and is able to bind the active site of fumarase
and inhibit its reactivity.
H
N
OH
HO2C
H
H
CO2H
fumaric acid
4.a
HO2C
H
H
CO2H
H
(S)-malic acid
4.b
HO2C
H
H
CO2H
(2S,3S)-2,3-dicarboxyaziridine
4.c
Predicting the biological activity of stereoisomers is very difficult. Stereoisomers are clearly different
based on configurational assignments of chiral centers, but they are also similar same molecular
formula, functional groups, and connectivity. So, should stereoisomers have different or similar
activity? In the end, the only way to be sure is through testing. Regardless, since 4.c aligns so closely
with both the substrate and product of fumarase, it would be reasonable to expect the enantiomer of 4.c
to match less well and therefore serve as a weaker inhibitor.
Examination of two different views of the Newman projections of the enantiomer of 4.c shows the
impact of the stereochemical changes. In the first Newman projection, the enantiomer still has nearly
trans carboxylic acids, but the front acid is on the left instead of the right. Likewise, the back acid
group is on the right instead of the left. In the second Newman projection, the acid groups are in the
right position, but now the NH no longer has the same orientation as the OH in (S)-malic acid. In the
enantiomer of 4.c, some spatial elements can be preserved at the cost of others. Therefore, 4.c would
likely not be as potent of an inhibitor of fumarase. The only way to know the activity of the
enantiomer with certainty would be to make and test the compound.
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H
N
CO2H
H
H
HO2C
CO2H
H
H
HO2C
enantiomer of 4.c
10
N
H
enantiomer of 4.c
Question 6
This is a simple plug and chug problem. The only trick is to make sure the concentration of Ki is
used in molar units (not millimolar).
o
Gdis
2.3RT log K i
o
Gdis
2.3 0.00199
(4.a)
kcal
mol
kcal
298K log 0.000022
6. 4
mol K
L
mol
The energy of dissociation has a positive sign, so dissociation is disfavored under the tested conditions
(i.e. binding is favored).
Question 7
Dissociation of an inhibitor-enzyme complex is entropically favored because the free enzyme and
inhibitor are more disordered than the complex. S for dissociation is therefore a positive number.
The TS term, however, would be negative. Therefore, in order for G to be positive, H must have
an even greater positive magnitude than G to offset the impact of a negative TS term.
None of these ideas is a surprise. If an inhibitor binds strongly, then it can form strong intermolecular
forces with the enzyme. Entropy always favors dissociation and disfavors binding. Therefore, in order
for binding to be favored overall, the intermolecular forces (enthalpic contributors) must be strong
enough to offset entropic factors.
Before finishing this question, a word of warning must be shared. Entropy can be very important in
the association and dissociation of drugs with their targets. This question ignores the impact of solvent
(water). Lots of water molecules can be involved during binding and dissociation, and those many
water molecules can collectively have a big impact on entropy. This idea gets fleshed out more
completely in Chapter 9.
Question 8
Before answering this question, one must convert all the [S] and V data into 1/[S] and 1/V values for
the Lineweaver-Burk plot. The Lineweaver-Burk graph of the [S] data is shown below with the best fit
line.
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1
1
1.16
0.0152
V
[S]
The r2 of the line is 0.99. Based on the y-intercept of the line, Vmax is 66 s-1. Km works out to be 76
mM. The high linearity of the data seems to indicate that the enzyme follows Michaelis-Menten
kinetics.
Question 9
Based upon the induced fit model, when a compound binds an enzyme, the conformation of the
enzyme changes. When a non-competitive inhibitor binds an enzyme at an allosteric site, the shape of
active site of the enzyme will likely be affected. It therefore seems unlikely that the substrate will have
the same affinity for both the free enzyme and the enzyme-inhibitor complex.
Similarly, when the substrate binds the active site, the shape of the allosteric site will probably change.
It therefore seems improbable that the inhibitor will have the same affinity for both the free enzyme
and the enzyme-substrate complex.
Independence of binding of both the inhibitor and substrate to the enzyme is a requirement for a pure,
non-competitive inhibitor. Because true independence of binding is rare, most non-competitive
inhibitors are mixed, not pure.
Question 10
For indole to show substrate-dependent behavior, it likely causes changes to the active site that affect
some substrates but not others. In the original Scheme 4.4, the substrate is depicted as a hexagon,
which is too large to fit into the active site if the inhibitor is bound. This would be an example of a
mixed, non-competitive inhibitor. The presence of the inhibitor affects the affinity of the enzyme for
its substrate. If the substrate is smaller, like the trapezoid below, then changes to the active site should
not impact substrate affinity. In this case, the inhibitor would possibly be a pure, non-competitive
inhibitor.
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not blocked
blocked
S
or
or
E
free
allosteric
site
S
changed
active site
active
site
12
bound
allosteric
site
What is not clear in the simple diagram is the assumption that the inhibitor must somehow be
preventing the conversion of the substrate to the product.
Question 11
The addition of inhibitor to an enzyme-substrate system gives an inverted V vs. [S] plot. Incremental
increases in [I] have a decreasing impact on the rate of substrate conversion.
Question 12
The name glutamate dehydrogenase certainly gives the impression that the enzyme is designed to
dehydrogenate glutamate to ketoglutaric acid. The Km values give a different impression. The
enzymes affinity for glutamate and NADP+ is less than ketoglutaric acid and NADPH. (The affinity
for NH4+ is lowest of all, but the concentration of NH4+ is higher than the other substrates/products.)
Based on Km values, the enzyme may run backwards better than forwards.
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13
Of course, enzymes are catalysts that help a system achieve equilibrium faster than without the
enzyme. Whether the enzyme runs net forward or backward depends the position of the system
relative to its equilibrium.
In practice, biological systems often do not ever reach equilibrium. As soon as a product is formed, the
product is used in a subsequent reaction. The rate of the reverse reaction is inconsequential because
the product never accumulates.
Question 13
Enzymes, and catalysts in general, undergo changes chemical and/or conformational during a
reaction and are reformed in their original state by the end of the process. A shovel, as a rigid object,
never changes. An archery bow might be a better illustration. The bow flexes through the process of
shooting an arrow, but it returns to its original state once the arrow has been launched.
Question 14
Competitive inhibitors of the same enzyme all bind the active site of the enzyme. They therefore tend
to share similar structural features. Non-competitive inhibitors, however, do not necessarily bind the
same position of an enzyme. Enzymes can have multiple allosteric sites, and inhibitors that bind
different sites will have different structures.
Question 15
Binding an enzyme at an allosteric site can cause conformational changes that may close the active site
and shut down an enzyme. If the conformational changes open an otherwise restricted active site, then
the binding agent would turn on the enzyme.
Chapter 5
Question 1
A smoothed curve of response vs. log [L] is shown below. The horizontal line is at 50% response, and
the vertical line is at log 1.63. This corresponds to log KD. KD = 43 M. Just glancing at the data
points, KD should fall somewhere between 30 and 100 M.
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14
Question 2
The data set gives a fairly normal looking, hyperbolic saturation curve.
When forced into a Lineweaver-Burk plot, the data give somewhat scattered line. Note that one data
point must be ignored (E = 0%) because it cannot be validly used in the Lineweaver-Burk equation.
The equation of the best-fit line is shown below.
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15
1
1
1.18
0.0019
% response
[ L]
Based on the y-intercept, Emax is approximately 530%. KD comes out to be 630 M. These values do
not match at all with the values seen in Question 1 or what one would expect from cursory inspection
of the data.
The Lineweaver-Burk approach to analyze receptor data is valid, but data in this example are not of
high enough quality to give good results. The analysis is not helped by having to discard one of the
data points because it cannot be inverted.
Question 3
A simple plot of the data points provided gives the V vs. [S] graph below.
Plotting 1/V against 1/[S] gives a Lineweaver-Burk plot.
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The equation for the line is

1
1
0.0010
0.038 .
V
[S]
Vmax is 26. Km is 0.026.

When V/Vmax is plotted against log [S], the following scatter plot is formed. This plot would normally
look like a sigmoid curve and be useful for determining log KD. In this case, the points seem to give a
nearly straight line. The best-fit line is shown, and the equation of the line is provided.
V
0.51log[S] 1.3
Vmax
Solving this equation for [S] at V/Vmax of 0.5 gives a value of 27. This is analogous to KD and is not
terribly far off from the Km determined from the Lineweaver-Burk plot. V/Vmax vs. log [S], however, is
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17
not a linear plot, and forcing it into a line is not a valid treatment of the data (regardless of how close
the number is to the desired outcome). What is missing in this log [S]-response plot is a full range of
log [S] values. A larger data set would properly show the regions in which the sigmoid has flattened
out. With the provided data, only the nearly linear region of the graph near the point of inflection can
be plotted.
The lesson is that most enzymatic studies are performed with a narrower range of concentration points
than receptor studies.
Question 4
To be completely accurate, in the presence of a receptor, some of the ligand is free [L] and the rest of
the ligand is bound to the receptor [LR]. The equation for total receptor is [Lt] = [L] + [LR]. Since the
concentration of receptor in any binding assay is very small relative to the concentration of the ligand,
the impact of the receptor on ligand concentration is generally ignored.
Question 5
The key to this question is to recognize that that y = 0 (bound/free = 0) at the x-intercept. Just set
bound/free to 0 and solve for bound.
B
bound
1
bound max
free
KD
KD
0
(5.12)
B
1
bound max
KD
KD
0 bound Bmax
bound Bmax
(at the x-intercept)
Bmax is reached only when y = 0, and y = 0 when the concentration of free ligand reaches infinity. For
this reason, Bmax is graphically a theoretical value.
Question 6
The new line will look very much like the line of the partial agonist alone. The only difference is that a
higher concentration of the partial agonist will be needed to affect a response. At high concentrations
the partial agonist will completely overwhelm the competitive antagonist.
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Question 7
There is nothing tricky about this question. Under Clarks occupancy theory, the response is directly
proportional to the percentage of the receptors that are occupied. Therefore, both the percentage of
response and occupancy are the same. See Figure 5.18.
% Response
% Receptor occupancy
20
20
40
40
60
60
80
80
Question 8
The first part of this question is just an application of Equation 5.8. For the full agonist questions, Emax
= 100%. For the very first case, set [L] equal to 0.01KD and solve for E.
E
[L]
E max
K D [L]
(5.8)
0.01K D
E
100% K D 0.01K D
E 0.99%
In a similar fashion, the percent responses for the other [L] values are 9.1, 91, and 99, respectively.
For the partial agonist questions, Emax = 35%. So, if [L] = 0.01KD
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0.01K D
E
35% K D 0.01K D
E 0.35%
For [L] = 10KD, E = 32%.

Question 9
Equation 5.28 is best equation for expressing both upregulation and downregulation. Upregulation and
downregulation involve changes in receptor concentration based on previous ligand exposure. Only
Equation 5.18 includes a term for receptor concentration.
[R t ][L]
E E 0 f
K
[L
]
D
(5.18)
Question 10
The allosteric model can handle both competitive and non-competitive antagonists. For competitive
antagonists, a sufficient concentration of agonist can overcome the effect of the antagonist on the
equilibrium of the tensed and relaxed states. For non-competitive antagonists, since the antagonist
binds the ligand at a site away from that of the agonist, the antagonists impact on the tensed-relaxed
equilibrium cannot be completely overcome by an agonist. The agonist may be able to cause a
response, but the noncompetitive antagonist, no matter what the agonist concentration might be, will
diminish the response. Note that this discussion is consistent with Figures 5.13 and 5.14.
Question 11
Agonist binding causes a physiological response. An antagonist decreases the response caused by an
agonist. The molecule is therefore neither an agonist nor antagonist. The molecule must bind an
inconsequential part of the receptor that has no influence on the receptors function. Just because a
molecule happens to bind a receptor does not mean that the molecule has an influence upon the
receptor.
Question 12
If the intrinsic activity (e) of a partial agonist is close to zero, the partial agonist effectively acts an
antagonist.
Question 13
Tyrosine kinase linked receptors are receptors that catalyze phosphorylations. Since the receptors have
catalytic activity, enzyme terminology is used on molecules that block the action of these receptors.
Question 14
Under rate theory, a full agonist must have a high koff value so that the compound may quickly re-bind
with the receptor. A partial agonist would have a lower koff value, which would in turn limit how
frequently the partial agonist can re-bind and trigger a response. In aggregate, the partial agonist
causes a sub-maximal response because binding occurs less frequently than with a full agonist.
Question 15
For this question, one needs Equation 5.13 (for the simple case of E = S) as well as a combination of
both Equations 5.14 and 5.15 (for E = 2S).
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E
e[ L]
E max
K D [L]
E
e[L]
2
E max
K D [L]
(5.13)
(Derived from Eq. 5.14 and 5.15)
All systems shown in Figure 5.23 achieve 100% response, so all involve full agonists (e = 1.0).
The table below gives ligand concentration and response data for a hypothetic receptor with a KD of 10
nM.
[L] (nM)
log [L]
%E (if E = S)
%E (if E = 2S)
0.1
1.0
0.99
1.98
0.3
0.52
2.9
5.8
1.0
0.0
9.1
18
3.0
0.48
23
46
10
1.0
50
100
30
1.48
75
100 (150)
100
2.0
91
100 (182)
300
2.48
97
100 (194)
1,000
3.0
99
100 (198)
Note that if E = 2S, then E calculates to be greater than 100%. This is impossible, so the %E is
capped at 100. These data points demonstrate the idea of spare receptors. At 50% occupation of the
receptor population ([L] = KD), the response for the E = 2S is already at 100%. The response pathway
is fully saturated, and half of the receptors are still unbound. These unbound receptors represent spare
receptors.
Plotting the two response columns against log [L] gives two lines. (For complete disclosure, some data
points were inserted between 3.0 and 10 nM to allow the E = 2S line to smooth properly.)
Erland Stevens
21
The E = 2S line climbs more steeply and abruptly flattens out at 100% response. The standard E = S
line has a smooth sigmoid shape.
The question has been fully answered, but the shape of the E = 2S line deserves more comment. Why
is the transition at 100% response so marked? Remember that the line for E = 2S is not a proper
function. It is actually two functions. The front half of the line, up to log [L] = 1.0, is simply E = 2S
as defined by the equation below.
E
e[L]
2
E max
K D [L]
As log [L] continues to climb, the percent response rises beyond 100%. This rise is very smooth if the
data is plotted. In our case, we declared any response greater than 100% to be impossible and capped
the response at 100% at higher log [L] values. The E = 2S line appears disjointed because it is
actually a merger of two functions.
Erland Stevens
22
Chapter 6
Question 1
The cytosine-guanine interaction involves three hydrogen bonds, while adenine-thymine has just two.
Because of this difference in number of hydrogen bonds, C-G interactions receive a greater weight in
determining Tm, as can be seen in the Wallace Rule (Equation 6.1).
Tm (o C) 2(# A / T) 4(# G / C)
(6.1)
Question 2
This problem requires assumptions on the duplex strand in terms of C-G and A-T composition. The
easiest assumption is to make the C-G equal to 50%, and A-T is 50%. In the case of odd numbers of
base pairs in the duplex, just split the difference and use a fractional number (e.g., 15 nucleotides = 7.5
C-G and 7.5 A-T).
For 10 base pairs
Tm 2(# A / T) 4(# G / C) 2 5 4 5 30o C
(6.1)
For 15 base pairs, Tm = 45 C. So the impact of lengthening the strand by five base pairs is an increase
in Tm by 15 C. Regardless of the length of the shorter strand, adding five base pairs of length is
predicted by Equation 6.1 to raise Tm by 15 C. That corresponds to a 3 C increase in Tm per
additional base pair.
Tm cannot scale linearly and indefinitely with duplex length. A duplex strand of 1,000 base pairs would
have a Tm of 3,000 C. Thus, the Wallace Rule has its limitations.
Question 3
The challenge to this question is to tautomerize compound 6.a in a manner that gives the right
orientation of hydrogen bond donors and acceptors to interact with guanine.
N
O
Br
O
NH
N
H
6.a
Br
H
O
N
N
H
tautomer
NH
H
H
N
N
H
N
N
H
N
O
H
tautomer-guanine
base pair
Question 4
In order to get a 1:1 mixture of products, the reaction must go through a symmetrical intermediate.
Like all mustards, the reaction starts with an intramolecular ring closure by the nitrogen on the alkyl
halide. The aziridine intermediate is then opened through attack by the thiosulfate anion. The two
Erland Stevens
23
carbons of the aziridine ring are virtually equally reactive. They differ only in isotope of hydrogen that
they bear (2H vs. 1H). The impact of the hydrogen isotopes is very small, so the ring can open either by
attack on the CH2 or the CD2 group. The products are formed in an approximately 1:1 ratio.
O D D
P
O
N
R H
(a)
O
P
O
N
R H
Cl
- HCl
D D
O
P
O
N
R
(a)
D D (b)
6.b
R = NHCH2CD2Cl
+H
O
S S O
(b)
O
6.d
O
P
O
N
R H
+H
aziridine
intermediate
S2O3-
S2O3D D
6.c
Question 5
The structure of bizelesin (6.e) is very similar to the product shown in Scheme 6.11, which is based on
the activity of adozelesin (6.44). Adozelesin starts with a reactive, three-membered ring that opens
when attacked by a nucleophile. Bizelesin does the same, but it must first form its three-membered
ring. The ring forms through attack of the 4-carbon of the phenol ring onto the carbon bearing the
chlorine atom. The ring is highly reaction. Opening the ring with a nucleophile both releases ring
strain and restores the aromaticity in the ring. Only one side of bizelesin is shown. Both sides must
react for bis-alkylation to occur.
Me
HN
Me
Cl
4
Nu
Me
Nu
HN
- Cl
N
R
HO
O
bizelesin
6.e
HN
N
O
H
Nu
N
R
HO
O
three-membered ring
intermediate
(analogous to 6.44)
Question 6
Equation 6.2 is undefined under two circumstances. One, if L (length of the duplex strand) is 0, then
Tm cannot be calculated because of division by 0. Since a duplex strand must have a non-zero length,
this circumstance is irrelevant. Two, if [M+] (concentration of monovalent cations) is 0, then log [M+]
is negative infinity. DNA is a negatively charged polymer and must include positive counterions to
maintain charge balance. Determining Tm with [M+] = 0 may be theoretically possible, but the
experimentally determined value would provide no understanding for the properties of DNA in a living
cell.
Erland Stevens
Tm ( o C) 79.8 18.5 log[M ] 58.4( X G X C ) 11.8( X G X C ) 2
24
820
L
(6.2)
Question 7
As the duplex strand length (L) approaches infinity, the last term in Equation 6.2 approaches a value of
0. From the text, the concentration of monovalent metal ions ([M+]) is 0.15 M. Finally, the question
tells us that the combined mole fraction of guanosine and cytidine (XG + XC) is 0.40. With this
information, we can solve for Tm. The answer is 89.8 C.
Tm ( o C) 79.8 18.5 log[M ] 58.4( X G X C ) 11.8( X G X C ) 2
820
L
Tm ( o C) 79.8 18.5 log 0.15 58.4(0.40) 11.8(0.40) 2 89.8 o C
(6.2)
(6.2)
Question 8
The sticky ends consist of four base pairs, and all four are A-T. Based on Equation 6.1, the Tm of this
strand should be just 8 C. That assumes that the presence of the additional base pairs do not affect the
Tm value.
Tm ( o C) 2(# A / T) 4(# G / C) 2 4 4 0 8 o C
(6.1)
Question 9
Both lysine and arginine are basic amino acids (see Table 4.1). Basic amino acids are protonated and
positively-charged at physiological pH. The high density of positive changes in histones allows the
proteins to bind especially strongly to the negatively charged backbone of DNA. Histones are
therefore ideal structures for the tight packing of DNA in the nucleus.
Question 10
Below is a graph of the Rosenthal type plot (r/Dr vs. r).
The best-fit line for this data is shown, and the formula for the line is provided below.
Erland Stevens
25
r
21.9 10 6 r 2.6 10 6
Dr
From this equation, replacing r/Dr with 0 (for the x-intercept) and solving for r provides a value of 0.12
netropsin molecules per DNA base pair. This is Bmax for netropsin.
Question 11
Below is a plot of the data from the table.
Just by looking at the data points in the table, one might estimate that the curve is approaching a
maximal Tm of nearly 15 C. That would put Tm at about 7.5 C. The value on the x-axis at this
point is approximately N/nt = 0.02. Note that entry 3 in the table corresponds almost exactly to these
values.
Question 12
Below is the plot of 1/Tm vs. 1/(N/nt) as inspired by the Lineweaver-Burk equation with a best-fit
trendline.
Erland Stevens
26
The equation for the best-fit line is provided below.

1
1
0.0018
0.060
Tm
N
nt
Based on the y-intercept value of 0.060, Tmmax is 17 C. That is not too far off our simple
interpretation of the data table in Question 11. If the slope of the line is 0.0018, we can use the
calculated Tmmax to determine that KD is 0.03. Again, this value is not far from the estimate in
Question 11. The point of this question is that reading values off a graph is not as accurate as letting
the data set speak for itself through a best-fit line. Of course, just because the data form a nice line
does not mean that the data are of high quality.
Question 13
The spectroscopic data be interpreted to show that the favored tautomer of 2-pyridone is 6.h because of
its max is closer to 230 nM than 270 nM. While this is not a true apples-to-apples comparison, if 2pyridone is in the keto form, then guanine may also favor the keto tautomer (6.f.).
Question 14
The full equilibrium of interest is shown below.
O
P
O OH
O
(acid)
6.l
+ H2O
O
P
O
O
O
+ H3O+
(conjugate base)
6.m
From this equilibrium, just use 7.4 for the pH and 6.6 for the pKa in the Henderson-Hasselbalch
equation. The concentration is the conjugate base (dibasic phosphate) is indeed greater than the acid
(monobasic phosphate) at physiological pH.
Erland Stevens
pH pK a log
7.4 6.6 log
0.8 log
[conj. base]
[acid]
27
Henderson-Hasselbalch eq.
[conj. base]
[acid ]
[conj. base]
[acid]
[conj. base]
6.3
[acid ]
Question 15
Antisense drugs act by binding a complementary oligonucleotide strand. Since DNA exists in a duplex
form, DNA is not free to bind antisense drugs.
Chapter 7
Question 1
Vd can be quickly determined with Equation 7.13. Do is 350 mg. Cmax is approximately equivalent to
Cpo. As always, watch the units.
Vd
Vd
Do
C po
(7.13)
350 mg
2.97 L
g
1 mg
1,000 mL
118
mL 1,000 g
1L
With a Vd of only approximately 3 L, infliximab is restricted to a very small volume of distribution. A

value of 3 L is comparable to just the plasma of a 70-kg patient. Considering the large molecular
weight of the drug, one should not be surprised that the drug does not cross the pores in the capillaries
and enter the interstitial fluid. Furthermore, the high molecular weight of infliximab prevents the drug
from diffusing across the cell membranes of the cellular components of whole blood. The drug should
be exclusively confined to the plasma.
Question 2
One approach to this question is through Equation 7.12.
k el
CL 0.693
Vd
t1 / 2
(7.12)
If the half-life for a drug is very long, then kel must be very small. By Equation 7.12, small kel values
arise from a low clearance, a high volume of distribution, or both. Based on Question 1, the Vd of
infliximab is extremely small, so the drugs long half-life (small kel) is indeed surprising. The only
possibility is that clearance for infliximab must be remarkably small. From Equation 7.8, clearance is
a function of both blood flow (Q) and extraction ratio (E).
CL Q E
(7.8)
Erland Stevens
28
Because blood flow to an organ is not a variable, the low clearance of infliximab must be attributable
to a low extraction ratio of the drug. A low hepatic extraction value (EH) indicates that the drug is
apparently inert to the metabolic enzymes of the liver. A low renal extraction value (ER) indicates that
the drug is either not filtered by the kidneys or it undergoes very extensive tubular reabsorption.
Infliximab is a massive drug 144,000 g/mol. Compounds of this size cannot undergo glomerular
filtration. If the kidneys cannot filter a compound, its renal extraction ratio should be essentially 0.
Consequently, renal clearance is 0, and kel is small despite a small value for Vd.
Question 3
As a drug more extensively distributes throughout the body and out of the central compartment
(plasma), its Vd increases. Regardless of a drugs distribution, renal elimination is restricted to the
amount of drug that is present in the plasma. Very little of an extensively distributed drug can be found
in the plasma at any given time, so the elimination rate constant due to renal filtration is very small
(half-life is large) for such a drug. Furthermore, hepatic clearance also only applies to any drug that is
found in the central compartment and passes through the liver. An extensively distributed drug would
have a low hepatic clearance as well.
Question 4
If a drug has a much greater kel than its metabolite, then the drug eliminates much more quickly than its
metabolite. A Cp-time plot for such a drug and metabolite is shown below.
Note that the drug has essentially completely eliminated while the metabolite is still present in the
plasma in appreciable quantities. With the drug virtually at Cp = 0, the metabolite is no longer forming
and is only undergoing elimination. At this point, the metabolite should follow first-order elimination
kinetics. A log [drug]-time plot for the late data points should give a line with a slope equal to the kel
of the metabolite.
Question 5
This question starts with just a plug-and-chug with a rearranged Equation 7.18. Concerns include
deciding on a mass of the patient (70 kg) and selecting reasonable units for the rate of infusion.
Erland Stevens
29
Because the oral dosing schedule is provided as mg/day, these would be good units for Rinf. A value for
kel must also be determined from the provided half-life.
C pss
Rinf
k elVd
(7.18)
Rinf C pss k elVd

Rinf 2.0
g 0.693
L
1,000 mL
1 mg
mg
66
70 kg
120
mL
53 d
kg
1L
1,000 g
d
Mathematically, determining the time required for the infusion to reach a target Cp is much messier
than the previous question. It requires rearranging Equation 7.17 to solve for time.
Cp
Rinf
(1 e kelt )
k elVd
e k elt 1
C p k elVd
Rinf
C p k elVd
ln 1
Rinf
t
k el
ln 1
1.0
(7.17)
g 0.693
L
1,000 mL
1 mg
66
70 kg
mL 53 d
kg
L
1,000 g
mg
120
d
ln 0.5 53 d
0.693
1
0.013
53 d
d
The time to reach just half of the desired Css is equal to the half-life of the drug 53 days. This is
clearly not acceptable; a patient should not need to wait months (literally) for a drug to reach
therapeutic levels. The solution to the problem would be to administer some sort of loading dose either
orally or by IV bolus.
This question is interesting mathematically. It demonstrates the fact that drugs with a long half-life are
impractical to administer by an infusion alone. From a practical perspective, one rarely administers
long half-life drugs by infusion. First, because the drug has a very long half-life, its Cp is fairly
constant and does not need to be continually replenished by an infusion. Second, very few patients are
connected to an IV line for months at a time to permit very long-term infusions.
Question 6
Plotting the provided data in the form of log Cp vs. time provides the following graph with trendline.
The equation of the best-fit line is ln Cp = 0.61t + 1.9. Since the slope is kel, kel must be 0.61 h-1.
Half-life is therefore 1.1 h.
Erland Stevens
30
Determing Vd requires just a little more work. The y-intercept of the line (1.9) is ln Cpo, so Cpo is 6.7
g/mL. This brings us to Equation 7.13, which calculates the Vd of the drug in this hypothetical 70-kg
patient to be 15 L. On a per mass basis, the Vd is 0.21 L/kg.
Vd
Vd
Do
C po
(7.13)
100 mg
15 L
g 1,000 mL
1 mg
6.7
mL
1L
1,000 g
Question 7
This question is more challenging because we need to fill in some gaps and make assumptions. The
chapter provides only a small number of methods for determining kab and F. F can be determined
through comparisons of AUC information between an IV bolus and an oral dose (Equations 7.22 and
7.23). These calculations require kab. kab can be calculated directly through Equation 7.28, but this
requires F. The only equation that isolates kab from F is the calculation of tmax (Equation 7.30).
Determining kab from tmax does require Cp-time data that hit very close to Cpmax. The data points for this
problem do show a clear tmax at 0.75 h, but the true tmax could easily be a little earlier or later than 0.75
h. Regardless, this is the best we can do with the data at hand. Therefore, we will assume that a tmax of
0.75 h is accurate for this drug.
t max
0.75 h
ln k el ln k ab
k el k ab
ln 0.61 ln k ab
1
0.75 k ab
h
(7.30)
Erland Stevens
ln 0.61 ln k ab
1
0.75 k ab
h
0.75 h
0.5625 0.75
31
1
k ab 0.4943 ln k ab
h
ln k ab 0.75
1
k ab 1.0568
h
Solving functions like this is not trivial. My approach is crude at best, but I normally use a spreadsheet
program to test a range of values for kab until the equation is solved. As a hint, kab values for most
drugs are larger than kel. This approach for determining kab gives a value of 2.8 h-1.
The last parameter to determine is F. We can use the theoretical y-intercept of post-absorption oral
data provided in the question. A plot of ln Cp versus time affords the following graph. Overall, the
data points form a typical curve for an oral drug and demonstrate both the absorption and elimination
phases. Only the very last points occur at a time during which absorption is essentially complete, and
only elimination is in effect. The last three points can be fit well to a line:
ln Cp = 0.752t + 2.13. (Note that if the data were perfect, the slope of this line would be identical to
the slope of the line in the previous question 0.61. Both lines should have the same slope since both
demonstrate first-order elimination of the same compound.)
The y-intercept of the line from the elimination data points is equal to ln Cpint. Cpint is theoretical
variable that is equal to a complex term that includes F (Equation 7.27). Based on the y-intercept of
2.13, Cpint is 8.4 g/mL. Use Equation 7.27 to determine F.
C py-int
g
8.4
mL
FDo
k ab
Vd (k ab k el )
1,000 g
1
2.81
1 mg
h
1,000 mL
1
1
15 L
(2.81 0.61 )
1L
h
h
F 100 mg
(7.27)
Erland Stevens
8.4
32
g
g
F 6.7
1.28
mL
mL
F 0.98
F works out to 0.98, so the drug has a bioavailability of 98%. Remember that the accuracy of this
calculation is limited by the accuracy of our estimate of kab. If kab is somewhere between 0.5 h and 0.75
h (perhaps 0.6 h), then our value of 0.75 h has a 25% error. That could explain why the slope of our
line in this question is so far off from the slope we observed in the previous question.
Question 8
This is a direct application of Equation 7.30.
t max
ln k el ln k ab
k el k ab
(7.30)
It is difficult to solve this kind of equation for kab. Perhaps the easiest way to determine kab is by trialand-error. Just try different values for kab with the known kel (0.693/2 h) until tmax works out to
approximately 1.6 h. kab is approximately 1.0 h-1.
Question 9
Equation 7.21 fails if kel = kab, which results in division by zero.
Cp
FDo
k ab
(e kelt e kabt )
Vd (k ab k el )
(7.21)
Question 10
As kab becomes very large Equation 7.23 simplifies significantly. The 1/kab term approaches 0, and the
kab/(kab kel) approaches 1.
AUC oral
1
FDo
k ab
1
Vd (k ab k el ) k el k ab
AUC oral
Do
Vd k el
(7.23)
(if kab = and F = 1)
This simplified form of Equation 7.23 is equivalent to Equation 7.10, which is the formula for AUC of
an IV bolus.
AUC
C po
k el
Do
Vd k el
(7.10)
If kab is infinite and F is 1, then the drug is instantaneously and completely absorbed into the central
compartment (the bloodstream). This exactly describes the situation of an IV bolus complete and
instantaneous absorption.
Question 11
The bioavailability of iron is likely close to 0.12 (1.0/8.0).
Question 12
Erland Stevens
33
A little thinking can greatly simplify this problem; refer to Figure 7.16. Each dose gives a higher peak
in Cp than the previous one until the system reaches a pseudo Cpss. Therefore, the Cpmax for the
azithromycin will occur after the oral dose on Day 5. The exact time on Day 5 can be determined
through Equation 7.30.
t max
t max
ln k el ln k ab
k el k ab
(7.30)
ln 0.0100 ln 1.88
2.80 h
0.0100 1.88
If Day 1 starts with the first oral dose (t = 0 h), then Day 2 begins at t = 24 h, Day 3 starts at t = 48 h,
Day 4 starts at t = 72 h, and Day 5 begins at t = 96 h. The overall tmax should occur 2.80 h into Day 5
or at 98.8 h.
To determine Cp at 98.8 h, the Cp contributions for each of the five oral doses need to be calculated
separately at the correct time interval with Equation 7.21. Do not forget that the dose on Day 1 is 500
mg.
Cp
dose 1
p
FDo
k ab
(e kelt e kabt )
Vd (k ab k el )
(7.21)
1
1.88
0.38 500 mg
mg
h
(e 0.0198.8 e 1.8898.8 ) 0.033

Day 1 dose (t =
L
1
1
L
31.1
70 kg (1.88 0.0100 )
kg
h
h
98.8 h)
C pdose 2
1
1.88
0.38 250 mg
mg
h
(e 0.0174.8 e 1.8874.8 ) 0.021

Day 2 dose (t =
L
1
1
L
31.1
70 kg (1.88 0.0100 )
kg
h
h
74.8 h)
C
dose 3
p
1
1.88
0.38 250 mg
mg
h
(e 0.0150.8 e 1.8850.8 ) 0.026

Day 3 dose (t =
L
1
1
L
31.1
70 kg (1.88 0.0100 )
kg
h
h
50.8 h)
C pdose 4
26.8 h)
1
1.88
0.38 250 mg
mg
h
(e 0.0126.8 e 1.8826.8 ) 0.034

Day 4 dose (t =
L
1
1
L
31.1
70 kg (1.88 0.0100 )
kg
h
h
Erland Stevens
C pdose 5
34
1
1.88
0.38 250 mg
mg
h
(e 0.012.8 e 1.882.8 ) 0.042

Day 5 dose (t = 2.8
L
1
1
L
31.1
70 kg (1.88 0.0100 )
kg
h
h
h)
Adding all five Cp values together gives a Cpmax of 0.156 mg/L (or 0.156 g/mL or 156 ng/mL).
Question 13
It is certainly possible that the concentration of azithromycin is greater in a patients tissues than in the
plasma. With a Vd of 31.1 L/kg, the Vd in a 70-kg patient is over 2,000 L. Azithromycin extensively
distributes into tissues and out of the central compartment. As azithromycin concentrates in tissues, it
is very possible for it to reach its minimum inhibitory concentration in an infected region.
Question 14
The scheme below depicts three compartments, and the third compartment is only accessible through
the peripheral compartment.
drug
intravenous
administration
central
compartment
(blood)
k21
elimination
k10
k12
peripheral
compartment
(tissues)
k23
k32
third
compartment
The scheme below shows three compartments. The third compartment is in equilibrium with both the
central and peripheral compartments.
elimination
k10
drug
intravenous
administration
central
compartment
(blood)
k21
k13
k31
third
compartment
k12
peripheral
compartment
(tissues)
k23
k32
Question 15
To do this problem, we need to assume a mass of the patient. As usual, 70 kg is a standard number.
Rearrangement of Equation 7.13 allows direct calculation of the required dose to reach the specified
LC50.
Erland Stevens
Vd
Do Vd C po 10
Do
C po
L
g 1,000 mL
1g
70 kg 5
3.5 g
kg
mL
1L
1,000,000 g
35
(7.13)
(7.13)
An IV bolus with 3.5-g dose is sufficient to reach the LC50 in a 70-kg patient. Remember that
immediately following an IV bolus, the dose is largely contained in the central compartment. The
central compartment certainly has a smaller volume than the full Vd of this drug. Therefore,
immediately following an IV bolus, the true Cpo of this drug is likely many times higher than the
calculated Cpo (which assumes instantaneous distribution see Figure 7.7).
Chapter 8
Question 1
If dextrorphan (8.b) is the primary metabolite, then the first metabolic reaction is a Phase I oxidative
dealkylation. Metabolite 8.b then apparently undergoes either Phase II sulfonylation to form 8.c or
another Phase I oxidative dealkylation (N-demethylation) to form 8.d.
Question 2
Below are examples from all five Phase I reactions.
Erland Stevens
NMe2
36
NHMe
oxidative
dealkylation
O
diphenhydramine
(Benadryl)
A.3
CO2H
N
CO2H
N
arene
oxidation
OH
OH
OH
OH
fexofenadine
(Allegra)
A.15
OH
Cl
montelukast
(Singulair)
A.16
N
OH
sulfur
oxidation
Cl
N
OH
CO2H
CO2H
S
O
Cl
OiPr
EtO2C
O
enalapril
(Vasotec)
A.120
OiPr
O
O
ester
hydrolysis
Me
N
H
Cl
fenofibrate
(Tricor)
A.111
Ph
OH
ketone
reduction
HO2C
Ph
CO2H
Question 3
Below are examples from all five Phase II reactions.
Me
N
H
N
O
CO2H
Erland Stevens
O O
S
NH2
amine
acetylation
O O
S
NH2
H2N
N
H
sulfanilamide
A.17
OH O HO
O
OH
O O
S
O
O
O
NH2
H
Me OH
H
Me OH
OH
NMe2
O
OH
Me
O
OH
NH2
NMe2
tetracycline
A.30
O
O HO
sulfonylation
OH
37
glucuronidation
HO
O
O
N
Me
OH
OH
CO2H
nalidixic acid
A.35
Me
O
OH
glycine
conjugation
Me
H
N
O
O
O
Me
gemfibrozil
(Lopid)
A.110
Me
O
F
O
OH
HN
ciprofloxacin
(Cipro)
A.36
CO2H
glutathione
conjugation
and
mercapturate HN
formation
F
N
OH
N
CO2H
S
HN
Me
O
Question 4
The liver and kidneys often compete for elimination of a drug. If the liver metabolizes any drug, then
less of that drug is eliminated by the kidneys. On the other hand, if the rate of metabolism by the liver
is slowed, then the kidneys will eliminate a larger fraction of the drug.
Question 5
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NC
F3C
HO2C
N
H O
O
OH
HO
NC
S
O O
F3C
S-bicalutamide
glucuronide
38
O
N
H HO
S
O O
OH
R-bicalutamide
oxidation
OH
The glucuronidation product is fairly straightforward. Glucuronidation tends to occur on alcohols, and
bicalutamide only has one OH group. The oxidation is harder to predict. Bicalutamide has several
potential sites for oxidation: either of the benzene rings, the NH group of the amide, the methyl group,
and the CH2 group next to the sulfone. Physiologically, the oxidation occurs adjacent to the fluorine on
the benzene ring.
Question 6
The data in Table 8.2 are not completely conclusive. None of the conditions can be directly tied to the
action of the kidneys. The liver is featured prominently in the table, and all liver problems
significantly lengthen the half-life of theophylline. Therefore, the liver likely plays a more important
role in clearing theophylline than the kidneys.
Question 7
Many of the Phase I redox reactions should be reversible. As an example, a ketone may be reduced to
an alcohol, and the same alcohol may be oxidized back to the original ketone. Acetylation (Phase II)
of an amine to form an amide can also occur in the opposite direction as the hydrolysis (Phase I) of an
amide to an amine.
Question 8
A compound with a higher polarity should concentrate in the parts of the body that are more polar,
such as the blood, and distribute less into lipophilic tissues. Since filtration by the kidneys occurs
exclusively on the blood, concentrating a compound in the blood (the central compartment) makes it
more subject to elimination by the kidneys.
In the context of Vd, a more polar drug should have a smaller Vd. Recalling Equation 7.12, if Vd
decreases, then the value for kel should increase. A higher value for kel indicates faster elimination and
a shorter half-life.
k el
CL 0.693
Vd
t1 / 2
(7.12)
Question 9
Based on Equation 7.9, CL is a function of blood flow (Q) and extraction ratio (E).
CLT QR E R QH E H
(7.9)
Blood flow through the kidneys (QR) is constant, but the extraction ratio (ER) can vary with the
properties of a drug. Raising a molecules polarity may minimize tubular reabsorption because the
more polar compound is unable to cross the tubule wall after it has been filtered by the glomerulus. A
drop in tubular reabsorption will increase ER and subsequently increase renal clearance (CLR) and total
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39
clearance (CLT). A compound with higher CLT has a higher value for kel and shorter half-life according
to Equation 7.12.
k el
CL 0.693
Vd
t1 / 2
(7.12)
Question 10
The liver can metabolize any drug that is transported by the blood. Since drug metabolites can
sometimes cause liver damage, any drug can potentially put the liver at risk. The full dose of an oral
drug, however, must pass through the liver to reach the general circulatory system. Therefore, the
exposure of the liver to orally-administered drugs is especially high. This answer follows the intent of
the question.
It is possible to undermine this question. Oral drugs tend to be fairly chemically stable because they
must survive the acidic environment of the stomach, enter the hepatic portal system, and pass through
the liver in concentrations high enough to reach therapeutic Cp levels. More highly reactive drugs,
especially alkylating agents used as cancer drugs (see Chapter 6), often cannot be administered orally
and are instead delivered by IV. The reactivity required for a DNA alkylating agent makes the
compound too unstable to survive oral administration. Highly reactive compounds, especially
electrophilic alkylating agents, are exactly the type of compounds that deplete glutathione reserves in
the liver and leave the liver vulnerable to damage.
Chapter 9
Question 1
The PDB data can be fit with Excel. A third-order polynomial fits the data considerably better than a
power, exponential, or logarithmic function. Excel is able to plot the original data and graph the bestfit trendline. (The most common trendlines linear, power, exponential, logarithmic poorly fit the
PDB data.) Excel, however, does not provide the coefficients in equation of the best-fit line with
enough significant figures to answer the question. Another application, like an applet from the web, is
needed. Regardless, the best-fit trendline and its equation as determined by Excel are shown below.
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40
The best-fit line determined by the recommended applet (third-order polynomial) is provided below.
structures 3.482392620769 1010
5.264582546500 10 7 year
2.652938916811 10 4 year 2
4.456230733864 year 3
Based on this equation, at the end of 2015 the number of structures in the PDB can be estimated to be
121,323.
structures 34,823,926,208
52,645,825.465 2015
26,529.38916811 ( 2015) 2
4.456230733864 ( 2015) 3
structures 34,823,926,208
52,645,825.465 2015
26,529.38916811 ( 2015) 2
4.456230733864 ( 2015) 3 121,323
Similarly, in 2020 the number of structures in the PDB is predicted to be 193,520.

Question 2
The first character can be selected from 10 possible values, and the other three characters can be
selected from 36 possible values (10+26). The total number of possible structures codes with the PDB
format is 466,560.
codes 10 36 36 36 466,560
While some may be able to solve the cubic equation below for the variable year, I cannot.
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466,560 3.482392620769 1010

5.264582546500 10 7 year
2.652938916811 10 4 year 2
4.456230733864 year 3
An alternative is to set up an Excel spreadsheet and calculate the number of structures predicted in
various future years. One can quickly hone in on the correct year through trial-and-error. Surveying
five-year intervals puts the target structure value between 2030 and 2035. A year-by-year analysis
indicates that the PDB will reach 466,560 structures sometime during the year of 2031. At that time,
all the PDB codes under the current labeling convention will be exhausted. There remains plenty of
time to work out a solution to this impending crisis.
year
structures
2025
289,486
2030
412,562
2031
440,725
2032
470,132
2035
566,091
Question 3
Below are the Ramachandran plots for 2HHB, 3HHB, and 4HHB.
2HHB
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3HHB
42
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4HHB
43
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According to the output text that accompanies the Ramachandran plots, structure 2HHB and 3HHB
have only 1.0% of their residues that fall outside the standard plot regions. Structure 4HHB, however,
has 5.1% outliers. Furthermore, 4HHB includes a D-amino acid. Natural amino acids have an L
configuration. Therefore, structure 4HHB contains more incorrect assignments than 2HHB and 3HHB.
Question 4
The dihedral angle is describes rotation about the C-N amide bond. The C-N bond of an amide has
two predominant conformations s-cis and s-trans. In these conformations, the C-N sigma bond gains
pi-bond character because of conjugation of the nitrogen lone pair with the neighboring carbonyl pibond. The possibility of resonance with the lone pair stabilizes both the s-cis and s-trans
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conformations in comparison to all other possible conformations. The s-cis conformation has a
dihedral angle of 0, and the s-trans conformation has a dihedral angle of 180.
O
O
N
O
N
O
N
H
N
H
s-trans
(180)
s-cis
(0)
Question 5
Two Newman projections showing the and dihedral angles are shown below. The magnitudes of
the angles are typical for an amino acid contained in a -helix. A value of 50 for gives high
separation between the R-group of the amino and the carbonyl oxygen and NH on the adjacent carbon.
Separation of the R-group is not as ideal for = 50, but the R-group is eclipsed (or nearly eclipsed)
with a very small hydrogen atom.
R
O
H
NH
OC
NH
-helix
OC
Glycine is a special amino acid because R = H. If R = H, the spatial, steric demands of the R-group are
dramatically decreased. The energetic benefit of minimizing the steric effects of a hydrogen atom is
small, so the idealized and values are not observed for glycine residues.
In the Ramachandran plots of Question 4, glycines (shown as ) have approximate dihedral values of
= 90 and = 120. The corresponding Newman projections are shown below.
HN
O
H
NH
R (H)
OC
R (H)
H
typical
glycine
CO
Both Newman projections place the R-group (R = H for glycine) in a relatively crowded position.
These placements are only reasonable because R is small for glycine.
Question 6
Below is the equilibrium of interest the deprotonation of salicylic acid to form its conjugate base.
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46
O
OH
base
OH
conj. acid
OH
conj. base
9.a
With the Henderson-Hasselbalch equation (Equation 9.1), biological pH (7.4), and the pKa of salicylic
acid (3.0), the ratio of the conjugate base to the acid can be readily calculated.
pH pK a log
7.4 3.0 log

4.4 log
[conj. base]
[acid]
(9.1)
[conj. base]
[acid ]
[conj. base]
[acid]
[conj. base]
25,000
[acid ]
At pH 7.4, the conjugate base is far and away the major form of the compound.
The three possible scenarios mentioned in the question are whether the carboxylic acid (actually in its
carboxylate form) is least likely to interact with a target through an ionic bond, hydrogen bond
acceptor, or hydrogen bond donor.
Ionic bond: The carboxylate is an ion and therefore could act through an ionic bond.
Hydrogen bond acceptor: The oxygens of the carboxylate group could accept a hydrogen bond
from a suitable hydrogen bond donor.
Hydrogen bond donor: The anionic carboxylate does not have an intact OH group and
therefore cannot interact as a hydrogen bond donor.
Question 7
As with Question 6, here is the key equilibrium. Note that at pH 7.4, salicylic acid (9.a) exists in the
carboxylate form. The equilibrium considering the phenol must start with the carboxylic acid already
deprotonated.
O
O
O
base
OH
conj. acid
O
conj. base
Following the same process as Question 6, one can calculate the ratio of carboxylate (phenol) to its
conjugate base.
pH pK a log
[conj. base]
[acid]
(9.1)
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7.4 13.6 log

6.2 log
47
[conj. base]
[acid ]
[conj. base]
[acid]
[conj. base]
1
[acid ]
1,600,000
The phenol is essentially completely in its acid form.

The three possible scenarios mentioned in the question are whether the phenol is least likely to interact
with a target through an ionic bond, hydrogen bond acceptor, or hydrogen bond donor.
Ionic bond: The phenol is neutral, so an ionic bond is highly unlikely.
Hydrogen bond acceptor: The oxygen of the phenol could accept a hydrogen bond from a
suitable hydrogen bond donor.
Hydrogen bond donor: The phenol could also act as a hydrogen bond donor.
The only improbable option is an ionic bond.

Question 8
Below is a Newman projection of 9.c.
H2N
CH2
H
H2N
H
O
O
trans-2-(3,4-methylenedioxyphenyl)cyclopropylamine
9.c
O
O
Newman projection
9.c
The Newman projection of 9.c shows an anticlinal relationship between the NH2 group and the
aromatic ring. The corresponding Newman projection of dopamine is shown below.
HH
H2N
H
OH
OH
anticlinal
Newman projection
of dopamine
9.b
The anticlinal conformation of dopamine is not a low energy conformation. It is a high-energy,

eclipsed conformation. Energetically, dopamine is more stable in other conformations, including any
staggered conformations. Dopamine therefore has a low probability of existing in the anticlinal,
agonist conformation.
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Question 9
The table below shows the molecular formula breakdown of the nine compounds in the question.
Entry
Compound
Formula
Non-hydrogen atoms
9.d
C18H20N3O3S
25
9.e
C35H36ClNO3S
41
9.f
C16H16ClNO2S
21
9.g
C22H28FN3O6S
33
9.h
C23H27Cl2N3O2
30
9.i
C18H21NO4
23
9.j
C33H35FN2O5
41
9.k
C21H25N3O2S
27
9.l
C18H19NOS
21
The average total number of carbon, nitrogen, oxygen, and sulfur atoms in this group of nine
compounds is 29.1. Thirty carbon, nitrogen, oxygen, and sulfur atoms does seem to be a fair number
for a typical drug. The range is values is broad with the highest having 41 atoms and the lowest
having 21. A typical drug size must be interpreted openly.
Question 10
Even a small fraction (0.1%) of all of drug space is still an inconceivable number of 1060. The number
of possible drugs from this pool of 1060 hits could very well run into the billions of compounds.
For students who are new to drug discovery, the search for a drug seems to be a hunt for the best
compound. While finding the best molecule would be ideal, the true goal of a drug discovery program
is to find a sufficiently active and safe drug. While there is only one best compound, there may exist
millions or billions or even more compounds that have the appropriate activity and safety to become an
effective and profitable drug.
Question 11
Multi-component reactions can very quickly generate large molecular libraries. The calculation for
potential Ugi products from building blocks available from the Sigma-Aldrich catalog is shown below.
products aldehydes acids amines isocyanides
products (600 0.80) (1,400 0.80) (800 0.25) (30 1.00) 3.2 10 9
In theory, reagents available from the Sigma-Aldrich catalog could be used to prepare a molecular
library containing approximately 3.2 billion compounds. That number is far greater than the current
number of molecules in the CAS registry. Even though this would be a massive library, its value for
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49
drug discovery may be poor. The molecular diversity of the library would be severely limited. It
would resemble the library with many members but low diversity in Figure 9.18.
Question 12
Scheme 9.7 is reproduced below.
M
HO
O
ester
linkage
coupling
OH
M
O
Wang resin
9.55
The functional group that connects the molecule of interest to the resin is an ester. Esters can undergo
reduction with hydride reagents, especially LiAlH4 and to a lesser degree NaBH4. Hydride reagents
transfer hydride (H) to the carbonyl of the ester and fragment the linker as shown. Once the molecule
of interest has been separated from the resin bead, the molecule is lost.
P
H
O
LiAlH4
O
H
O
O
broken connection
between the resin
and the molecule
of interest
Questions 13
The mechanism is shown below starting with the complete structure of 9.65. The key feature in the
resin linker that allows the benzodiazepine to be cleaved is the substitution of three electron-donating
OR groups on the aromatic ring. These three groups give the ring enough electron density to eject the
protonated benzodiazepine as a leaving group.
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50
R2
R2
A H
H-A
MeO O
N
R1
P'
R3
N
OMe
R3
R1
resin-bound
diazepines
9.65
R2
MeO
H
MeO O
P'
P'
N
O
OMe
R2
R1
HO
OMe
R3
R1
tautomerization
R2
HN
R1
R3
Question 14
Compound D3 should have three tags, tw, tx, and tz, on its resin. Compound B2 should have just two
tags, tw and ty, on its resin. These tags should be unique to each of these compounds.
Question 15
Deconvolution of a hit from the 27-member library would require the synthesis of six compounds. The
identity of the reagents used in the last step of making the hit is known. Three cataloged resins from
the second step one resin that last reacted with 1, one from 2, and one from 3 would need to be
carried through the last step to determine whether 1, 2, or 3 gave the hit. Three cataloged resins from
the first step would need to be carried through the second and third step to fully characterize the hit.
As a result, a total of six final compounds are prepared.
In general, deconvolution of a multi-step synthesis will require the synthesis of a number of
compounds equal to the number of building blocks used in the all steps but the last. For a three-step
synthesis with x, y, and z buildings blocks, x + y compounds would need to be prepared for
deconvolution of a hit. For a four-step synthesis with m, n, o, and p building blocks, m + n + o
compounds would need to be prepared for deconvolution of a hit.
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Chapter 10
Question 1
The phrase essentially one product leaves room for interpretation, but here is an analysis of the three
reactions.
E2 elimination of HBr with a base

This reaction will likely give a mixture of products. The elimination involves removal of a hydrogen. The compound contains two different -hydrogens, each of which will give a
different product. Furthermore, one of the elimination products can form as either an E- or Zisomer. In total, three products may form in significant quantities.
O
Z
MeO
O
MeO
OMe
Br
OMe
product 1
MeO
product 2
OH
OMe
O
via
MeO
MeO
OMe
OMe
product 3
OsO4-catalyzed dihydroxylation of an alkene

This reaction should form just one product. It will be a mixture of enantiomers, but almost all
libraries consider racemic mixtures to be a single compound for screening purposes. If a
racemic mixture gives high activity in a screen, confirmation screening and deconvolution will
require single enantiomer testing.
Br
Br
OH
OH
Diels-Alder cycloaddition of a diene with acrylonitrile

Diels-Alder cycloadditions tend to be highly regioselective (1,2- vs. 1,3-product) and
diastereoselective (endo vs. exo). This reaction is no exception. Predominantly one product
will be formed. As with the dihydroxylation in the previous reaction, the cycloaddition will
form a racemic mixture.
OCH3
CN
OCH3
NC
+
Ph
Question 2
Ph
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52
Both compounds have complicated, polycyclic structures with multiple stereocenters. Furthermore,
compound 10.b has a fairly high MW (425 g/mol) for a lead compound. It would be difficult to
synthesize analogues. This can be a significant challenge for natural products. While these structures
might be too complex to serve as good leads, they may still be useful for drug discovery. Medicinal
chemists can sometimes reduce an active molecule down to its minimal core. This core is called a
pharmacophore and normally has a much simpler structure than an original hit or lead.
Pharmacophores and their use in drug discovery are covered in Chapter 11.
Question 3
Below are some possible consequences of problems in storing, handling, and dispensing compounds in
a molecular library.
Evaporation of the stock solution of a library member

If a solution has evaporated to a smaller volume, then the concentration of the compound in the
solution will be higher than expected. The compound will erroneously be recorded at its
original, lower concentration, but its activity will reflect its elevated concentration.
Evaporation of the solvent in the stock solution will make the library member seem higher in
activity than it actually is. Note that precautions are taken to minimize evaporation. Storage
solvents tend to have a low vapor pressure, and samples can be stored at low temperatures.
Degradation of the compound during long-term storage

If a compound degrades, then its concentration will be lower than expected. The assay will
underreport the activity of the molecule. If the compound barely misses the threshold activity
level of a hit, then the underestimation of activity may cause the degraded compound to be
missed altogether in the assay. Degradation of compounds during storage can be a serious
problem even though compounds are stored at low temperature.
Random error in dispensing of small volumes

Very small volumes of liquids can be difficult to dispense reproducibly with robotic liquid
handlers. If the inaccuracies are random, then the impact cannot be predicted. In practice,
dispensing errors tend to provide too small of a volume of liquid than too large a volume.
Impure sample in the library

If a compound is impure (and yet assumed to be impure), then its actual concentration is lower
than what is expected. This results in the activity of the compound being underreported in the
assay. Therefore, impure compounds run the risk of being missed in a screen. An impure
sample is very similar to a degraded sample.
Question 4
This is a high school chemistry question.
mass molecules
mass 1.39 10 7 molecules
mole
grams
molecules mole
1 mole
153 grams
23
1 mole
6.02 10 molecules
mass 3.53 10 15 grams 3.53 10 -18 kg
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53
This number is miniscule compared to the 30 large atom library. Why skimp at just one molecule of
each library member? Go wild and have 10 molecules of each. The main difference is the number of
members in the library 107 vs. 1063.
Question 5
Here is Equation 10.1.
o
G bind
2.3RT log K A 2.3RT log
1
2.3RT log K D
KD
(10.1)
Equation 10.1 evaluates to a negative number for Gbind because log KD gives a negative value. This
occurs because KD normally has a value of less than 1. Remember that KD for a receptor is determined
by the equation below.
KD
[ R ][ L]
[ RL]
KD evaluates to less than one because the equilibrium favors the receptor-ligand complex over the free
receptor and unbound ligand. If the equilibrium favored the free receptor and ligand, KD would
become greater than 1, log KD would be positive, and Gbind would be positive.
Of course, good drugs tend to bind strongly, not weakly. The target KD (same as EC50 under Clarks
occupancy theory) for a drug that binds a receptor is in the range of 10 nM. So, the binding energy for
such a compound is
o
G bind
2.3RT log K D
o
G bind
2.3 0.00199
(10.1)
kcal
mol
298K log 1 10 8
mol K
L
o
G bind
10.9
kcal
mol
If KD is greater than 1, then EC50 is also greater than 1. The units on EC50 are mol/L. In other words,
the concentration of such a compound (KD > 1) to achieve a 50% response from a receptor would need
to be greater than 1 M. That would be a preposterous concentration for a drug.
The reason that positive binding energies are not encountered in the discussion of hits, leads, and drugs
is because compounds with positive binding energies have no possible value to a drug discovery
program.
Question 6
The breakdown of the compounds is below. Entries 2 and 7 both violate Lipinskis rules with regard to
MW and log P.
Entry
Compound
Formula
MW
log P
H-bond
donors
H-bond
acceptors
10.c
C18H20N3O3S
345
0.6
10.d
C34H34ClNO3S
586
7.9
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54
10.e
C16H16ClNO2S
322
2.5
10.f
C22H28FN3O6S
482
2.4
10.g
C23H27Cl2N3O2
448
4.5
10.h
C18H21NO4
315
0.3
10.i
C33H35FN2O5
559
5.7
10.j
C21H25N3O2S
384
2.8
10.k
C18H19NOS
297
4.0
Comments
Esomeprazole The NH nitrogen does not count as a hydrogen bond acceptor because that
nitrogens lone pair is involved in the aromaticity of the ring.
Clopidogrel The OR group of esters is not considered to be a hydrogen bond acceptor

because it contributes electron density to the carbonyl.
Rosuvastatin The NMe nitrogen is part of a sulfonamide and is not included in the hydrogen
bond acceptor tally.
Aripiprazole The NH nitrogen, which is part of an amide, is not considered to be a hydrogen

bond acceptor.
Atorvastatin The ring nitrogen and NH of the amide are not counted toward the number of
hydrogen bond acceptors.
Question 7
Lipinskis rules predict cell membrane permeability and oral bioavailability of a drug. If a drug is
administered by inhalation, then its oral bioavailability is not of any consequence.
Question 8
The possible explanations attributed the extra binding energy to either the binding of the CH2CH2 to
the enzyme or some other impact of changes introduced by the tether. In Chapter 9, the potential van
der Waals attraction from a single CH2 group is 0.8 kcal/mol. Therefore, two CH2 groups would
provide 1.6 kcal/mol of binding energy. Based on this information, the simplest explanation for
addition binding energy seems to be van der Waals attraction between the CH2CH2 tether and the
enzyme.
Chapter 9
The formula for ligand lipophilicity efficiency is shown below.
LLE log IC 50 log P
(10.2)
The four compounds compare as follows

Entry
Number
log ED50
clog P
LLE
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55
10.l
6.96
2.97
3.99
10.m
4.49
0.08
4.41
10.n
6.14
2.76
3.38
10.o
7.02
3.35
3.67
Despite being the least potent based on its ED50 value, compound 10.m is the most attractive hit based
on its LLE score.
Question 10
Privileged structures can be very fruitful areas for searching for biologically active compounds. From
a drug discovery perspective, however, it can be very difficult to find areas within privileged structures
that have not been thoroughly explored by other companies and researchers. Finding undiscovered
activity from privileged structures is a challenge, and any new activity can be hard to protect with
patents.
Question 11
The four compounds compare as follows
Entry
Number
log ED50
Gbind
(kcal/mol)
n
(atoms)
LE
(kcal/mol/atom)
10.l
6.96
9.49
20
0.47
10.m
4.49
6.12
19
0.32
10.n
6.14
8.37
23
0.27
10.o
7.02
9.57
19
0.50
Compounds 10.l and 10.o stand out as having particularly large LE values.
Question 12
For a typical drug
LE
LE
2.3 0.00199
2.3RT log K D
n
(10.a)
kcal
298 K log 10 8
kcal
mol K
0.36
30 atoms
mol atom
If this is the LE value for a typical drug, then 10.l and 10.o stand out even more as very strongly
binding compounds based on their size (number of non-hydrogen atoms).
Question 13
For a typical drug
LLE log IC 50 log P
(10.2)
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56
LLE log 10 8 log P 8 5 3
A LLE value of 3 should be seen as a minimum value since log P should ideally be less than 5.
Question 14
The structure of compound 9.74 is shown below.
Ph
O
H
N
O
NH2
H
O
O
9.74
This compound is fantastically complex polycyclic with several stereocenters. Furthermore, the
molecule has a MW of 430 g/mol. This compound is somewhat larger than an ideal lead (MW 350
g/mol), and its complexity would hinder analogue synthesis.
Question 15
Polar surface area is exposed molecular surface that should interact favorably with a polar solvent,
most notably water. As a compound crosses a cell membrane, the availability of water will be
negligible. The polar surface area of the molecule will need to interact with the lipophilic tails of the
phosphodiesters of the lipid bilayer. These interactions will be weak in comparison to salvation in
water, so a compound with a large amount of polar surface area will favor being dissolved in a polar
medium.
Chapter 11
Question 1
MPPP does fit the morphine rule. It has (a) a phenyl ring next to (b) a quaternary carbon bearing (c) a
tertiary aminoethyl chain. When MPPP is redrawn to resemble the compounds in Figure 11.1, the
structural analogies between the morphine pharmacophore and MPPP are clear. Indeed, MPPP is
nearly identical to meperidine except that the carbonyl and oxygen of the ester have been swapped.
This type of reverse ester analogue is another example of a bioisostere, a few examples of which can
be seen in Table 11.5.
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57
(a)
(c)
(b)
morphine
pharmacophore
11.2
meperidine
(Demerol)
analgesic
11.3
MPPP
11.a
Question 2
trans-2-(3,4-Methylenedioxyphenyl)cyclopropylamine (11.c) preserves very roughly an anti
orientation of the amino and the aromatic ring. Highlighting the key elements of dopamine within the
structures of 11.d and 11.e reveals that the amine and hydroxylated ring are held roughly syn (lie on the
same side of the plane defined by the carbons and hydrogens of the ethylene group) to one another in
11.d. The amine and hydrolyated ring are approximately anti to one another in 11.e. If this
observation is correct, then the anti orientation of 11.c is more closely approximated by 11.d than 11.e.
Compound 11.d would therefore more likely have agonist activity than 11.e.
OH
OH
OH
H2N
Me
OH
OH
Me
OH
dopamine
11.b
11.d
11.e
amine and hydroxylated

ring are roughly syn
amine and hydroxylated

ring are roughly anti
Question 3
Although compounds from Figure 11.5 are mentioned in the question, their structures are not relevant
to the conformational restrictions in 11.f. All of the structures that have an impact on this question are
shown below.
S
Cl
Cl
NMe2
chlorpromazine
(Thorazine)
antipsychotic
9.27
NMe2
Z-analog
active
9.28
S
Cl
Me2N
Cl
NMe2
E-analog
inactive
9.29
inactive
11.f
From 9.28 and 9.29 it would seem that the amino group must be able to position itself to the left of the
structure in order for the compound to be active. Compound 11.f shows that forcing the amino group
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58
too far to the left is not favorable. Therefore, the problem is how to restrict the amino group to the left
without forcing it too far.
The two compounds below try to address this problem. Both keep the general features of 9.27-9.29.
The amino group is connected to the ring nitrogen through a tether of three carbons. Rings are used to
hold the amino group in a restricted volume. The positions of the amino groups in both proposed
compounds are consistent with available conformations of the aminopropyl chain of 9.28, the active
analogue of chlorpromazine.
S
Cl
1
3
NMe2
Cl
2
Me2N
A challenge for both of these compounds is that the additional ring would likely make them much
more difficult to synthesize.
Question 4
The compounds in the table reveal a few trends. The acid is vital for activity (entry 1 vs. 2). The
length of the tether to the SH cannot be changed (entry 1 vs. 4). The SH group is needed for activity
(entry 1 vs. 7). Based on the table data, the likely pharmacophore of captopril has the structure below.
H
N
HS
O
CO2H
captopril
pharmacophore
From this core structure, a large number of reasonable analogues are possible. The table below shows
some examples with explanatory text.
Entry
Structure
HS
HS
Me
N
CO2H
Rationale
Adding N-substitution may restore some lost activity without
introducing any more bulk than was present in the original
compound.
Changing the size of the ring may improve binding geometry.
N
O
CO2H
HS
N
O
CO2H
HS
N
O
CO2H
Connecting the methyl group to the ring may hold the

compound in an ideal geometry for binding (or it might make
the ideal conformation inaccessible). The new connection
introduces a new stereocenter, and both stereochemical
configurations would likely be explored.
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Cl
HS
N
CO2H
HS
NH
N
N N
N
O
CO2H
HS
N
CO2H
HS
N
O
In theory, this is a reasonable compound to try. It is a simple

isosteric replacement of the Me with a Cl atom. In reality, this
compound would almost certainly be too unstable chemically to
be a drug candidate. Analogues must be chemically feasible.
This is a bioisosteric replacement of the carboxylic acid with a
tetrazole ring.
Me
HS
59
This compound is a combination of entries 1 and 3 add a ring

and cap off the nitrogen.
This very compact structure challenges the idea that the SH
should be extended away from the carbonyl. While the structure
looks very different from captopril, the SH group is still
removed from the carbonyl by just two carbons. As with a
previous entry, this change introduces a new stereocenter, and
both configurations should be tested.
CO2H
Many other reasonable analogues are possible.

Question 5
The six isosteric analogues of morphine are shown below. Other possibilities exist. The replacement
atoms are bolded to make them more obvious.
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HO
univalent
isosteres
HO
O
N
divalent
isosteres
NH2
HO
HO
HO
HO
O
ring
isosteres
Cl
H2C
HO
HO
60
N
HO
HO
O
N
HO
N
HO
This morphine example is not the best to demonstrate univalent isosteres. Replacing an N-CH3 with an
N-NH2 or (far worse) an N-Cl would be an uncommon and unstable substitution. In this example,
however, these are the only possible replacements. A more representative univalent isosteric
replacement would be to substitute a CH3 group on an aromatic ring with an NH2 or Cl.
Question 6
Everything behaves normally until OH and NH2 groups are placed in the ortho position. What is
unique about OH and NH2? Both are hydrogen bond donors and acceptors. Furthermore, the
CH2CH2OH side chain on the ring of 11.g can undergo hydrogen bonding. If the side chain undergoes
hydrogen bonding with an ortho substituent, then the chain will be folded back toward the ring. This
could drop the activity of the analogue if strong binding requires the chain to be fully extended away
from the ring.
H
O
O
H
O H
O
intramolecular hydrogen
bond restrains the
CH2CH2OH side chain
Question 7
Sulfur is different because it is on the third row of the periodic table. Atoms get much larger in terms
of atomic radius down a column of the periodic table. The atomic radii () of carbon (0.77), nitrogen
(0.70), and oxygen (0.66) are fairly close in magnitude and all considerably smaller than sulfur (1.04).
A larger atomic radius gives rise to larger bonds. Since sulfur forms significantly longer bonds than
carbon, nitrogen, and oxygen, sulfur is a poor isosteric replacement for the other three atoms.
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Question 8
The key to this question is lining up the functional groups on the two molecules ritonavir (11.75) in
Figure 11.19 and A-74704 (11.74) in Figure 11.18. If you inspect the left sides of the two molecules,
both contain an aromatic ring connected to a CH2 group and then a carbamate (NH-CO-O). The next
group is a non-polar side chain. In 11.74 this group (isopropyl) fills pocket P2'. Presumably, in 11.75
this group (benzyl) will also fill pocket P2'. At this point, all the other non-polar groups can be
aligned. Moving right-to-left on compound 11.75, the next benzyl group fills P1', the isopropyl fills
P1, and the isopropyl on the thiazole ring fills P2.
Only the hydrogen bonds remain. Again, moving right-to-left on 11.75, the first hydrogen bond
acceptor after the P2' group is the OH. This likely forms a hydrogen bond to the free water molecule in
the HIV1 protease-binding pocket. Next down the line is an amide which can act as either a hydrogen
bond acceptor or donor. Lastly, the urea carbonyl can form the second hydrogen bond with the active
site water molecule.
N
H
Ph
N
H
OH
P1
P2
Ph Ph
H
N
N
H
O
N
H
H
N
Ph
P1'
A-74704
11.74
P2'
H-bond
donor/acceptor
water
Ph
O
S
N
Me
N
H
ritonavir
(Norvir)
11.75
P2'
P1
H
N
O
HO
Ph
H-bond
N
H
O
S
water
P1'
P2
Just because the groups can be aligned in this manner does not mean that this is indeed how the
molecule interacts with the binding pocket of the enzyme. Regardless, this is a reasonable guess as to
how ritonavir binds HIV1 protease.
Question 9
The binding energy for the 100 nM compound is 9.55 kcal/mol.
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62
o
G bind
2.3RT log IC 50
o
Gbind
2.3 0.00199
(10.1)
kcal
kcal
298 K log 10 7 9.55
mol K
mol
The binding energy for the 10 nM compound is 10.9 kcal/mol.

o
Gbind
2.3 0.00199
kcal
kcal
298 K log 10 8 10.9
mol K
mol
The impact of a magic methyl would need to be 1.35 kcal/mol.

Question 10
Instead of just adding a methyl to steer the sulfide chain into the correct conformation, the entire
system could be locked into place with a ring. Either a five- or six-membered ring would be
reasonable. The carefully planned pH effects from the additional alkyl substitution in cimetidine
should be replicated in the new analogue.
Me
HN
S
N
H
N
NHMe
N
cimetidine
(Tagamet)
H2 antagonist
11.35
HN
CN
H
N
NHMe
N
CN
A problem with adding additional substituents to restrict conformations is that the new groups create
steric bulk that can prevent proper binding.
Question 11
The effect of the magic methyl is indeed magical. Getting a full 1.35 kcal/mol for a single methyl
group is very impressive and requires the methyl group to virtually perfectly fit within a pocket.
Question 12
The equilibrium is shown below.
H
H3C N H
H
H
H3C N
H
+ base
+ conj. acid
The ratio of the conjugate base (CH3NH2) to acid (CH3NH3+) is about 1 to 1,600.
pH pK a log
[conj. base]
[acid]
7.4 10.6 log
[conj. base]
[acid ]
3.2 log
[conj. base]
[acid ]
[conj. base]
1
[acid ]
1,600
(9.1)
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That corresponds to approximately 0.06% in the conjugate base form.

Question 13
Scheme 11.3 is reproduced below. For a substituted imidazole (like histamine) only 3% of the mixture
is in the protonated (acid) form, so 97% is the conjugate base. For burimamide, 40% is protonated as
the acid and only 60% is the conjugate base. For metiamide, 20% is protonated and 80% is not. This
is all the necessary information for the calculation.
R
HN
distal tautomer
11.42
R
HN
NH
conjugate acid
11.43
NH
proximal tautomer
11.44
For histamine
pH pK a log
[conj. base]
[acid]
7.4 pK a log
(9.1)
97
3
pK a 5.9
For burimamide
7.4 pK a log
60
40
pK a 7.2
For metiamide
7.4 pK a log
80
20
pK a 6.8
Question 14
The pKa of dicyanomethane, CH2(CN)2, is approximately 12. With an alkyl substituent off the CH2
group, that value should increase a small amount. The pKa of this group is very close to that of an
alcohol (16). In drugs, alcohols often act as hydrogen bond donors or acceptors. With acidity so close
to an alcohol, the dicyanomethyl group should have some ability to donate a proton. Furthermore,
partial deprotonation will allow the dicyanomethyl group to act as a proton acceptor as well.
Question 15
The isosteres are shown below. Exact modifications for the C- and N-termini can vary. Furthermore,
an exact retroinverso isostere for the proline residue is impossible.
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H2N
angiotensin II
(original form)
NH
H3N
N
H
O
N
H
N
O
O
N
OH
N
O
Ph
NH
OH
NH
O
O
HO
angiotensin II
(retroinverso form)
HO2C
N
O
HN
H2N
H
N
Ph
NH
NH2
H2N
N
H
N
H
N
HN
H
N
H
N
HO2C
HN
H
N
HO2C
angiotensin II
(peptoid form)
OH
NH
O
64
N
H
HN
O
H
N
O
N
H
N
O
H
N
O
N
H
Ph
N
O
Chapter 12
Question 1
If a Hansch analysis minimally requires five compounds per molecular descriptor, then Equation 12.a
with three descriptors should require 15 compounds in the training set. Only nine compounds were
used to construct the Hansch equation.
Question 2
Lipophilicity often follows a parabolic trend as shown in Figure 12.3 (below). A molecule needs to
have sufficient polarity to dissolve in aqueous media and be transported by the blood, but it also needs
sufficient lipophilicity to diffuse across membranes. This polarity/lipophilicity balance can be
approximated mathematically by including both a first power and second power term for lipophilicity.
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Question 3
QSAR data is impacted in two important ways by accuracy of screening data. First, trends generated
by a Hansch equation can only be as accurate as the activity information in the training set. If the
training set contains much error, then the resulting Hansch equation will be fit to the erroneous data.
The fit will likely be poorer. Second, use of an error-filled Hansch equation to predict the activity of
previously unknown compounds will also be of lower quality. The old adage Garbage in; garbage
out. definitely holds in Hansch equations.
Question 4
There are many ways to approach this problem. One is to consider how a result with a 4-Cl analogue
might be misleading and steer the user to the wrong branch. Looking at the different outcomes with a
4-Cl group, there are three options.
4-Cl analogue is less potent

The Cl either introduces an unfavorable steric interaction or acts as an EWG when an EDG is
better. Analogues down this branch test either replacing the 4-Cl with an EDG group (4-OMe
or 4-NMe2) or moving the Cl atom to the 3-position to avoid steric problems at the 4-position.
4-Cl analogue is equipotent

This branch seems to emphasize steric bulk. The options on this branch either maintain bulk at
the 4-position (4-Me or 4-t-Bu) or move the substitution to the 3-position.
4-Cl analogue is more potent

This branch emphasizes the electron-withdrawing nature of the Cl group. All analogues in this
branch place strong EWGs or multiple EWGs on the ring.
One possibility for a misstep would be if the 4-Cl analogue showed higher activity because the 4-Cl
was filling a binding pocket, not because it was acting as an EWG. With higher activity the tree will
steer the chemist to explore more and stronger EWGs when perhaps larger substituents (4-t-Bu) would
provide the most active compound.
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66
Question 5
Here are the two key equations.
ln k
Ea
ln A
RT
(12.c)
Es(R) log k R log k CH3 log
kR
k CH 3
(12.17)
Equation 12.17 can be rewritten to work with natural logarithms by adding a factor of 2.3.
E s(R) 2.3 ln k R 2.3 ln k CH 3
Substitute Equation 12.c into Equation 12.17.
E s(R)
E aCH3
E aR
R
2.3
ln A 2.3
ln A CH 3
RT
RT
Es(R)
E aR
E aCH3
R
2.3
ln A
ln A CH 3
RT
RT
The value for A, the pre-exponential factor, is different for every reaction. In this case, however, all the
reactions are very similar, so the A values for each are nearly identical. Therefore we can drop this
term from the discussion. Isolating the Ea terms reveals that Es is indeed a function of Ea and directly
proportional to Ea.
E R E CH 3
E s(R) 2.3 a a
RT
RT
E R E CH 3
E s(R) 2.3 a a
RT
RT
Es(R)
2.3
E aR E aCH 3
RT
Es(R)
2.3 E a
RT
E s(R) E a
Question 6
The NH2 group is a very strong electron-donating group as reflected by its large and negative -value
of 0.660. In order for the -value to become positive, the NH2 group must somehow become
electron-withdrawing. The easiest way for this to happen would be for the NH2 group to be protonated
to an NH3+ group.
In general, -values are used to examine groups on an aromatic ring. Aromatic amines tend to have a
pKa around 5. Therefore, if the compound is in a weakly acidic environment with a pH of 5 or less, the
most common form of the amine will be as the protonated conjugate acid (R- NH3+).
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Question 7
The Hansch equation based on just log P is given below.
log BC 0.54 log P 0.12
n = 8, r = 0.95
The Hansch equation based on both log P and (log P)2 is not meaningfully improved.
log BC 0.94 log P 0.04(log P ) 2 0.76
n = 8, r = 0.95
Addition of the (log P)2 term is not helpful. This is very surprising since lipophilicity normally shows
a parabolic relationship with activity. This study, however, is not about biological activity. It is about
how the insecticides concentrate into trout tissue. The more lipophilic a compound is, the more it
should concentrate. That is exactly what the first equation (log P alone) states.
There is another possibility. It is possible that the training set of insecticides in this study do not have a
broad enough range of log P values to allow the parabolic relationship of lipophilicity to
bioconcentration to be seen. For example, if an insecticide were so highly lipophilic that it had zero
solubility in lake and stream water, then it might be reasonable to see very low levels of
bioconcentration of that insecticide in wildlife.
Question 8
Below is the Hansch equation from the provide parameters.
log AA 0.28G 0.35 log P 4.75
n = 9, r = 0.90
Because the sign on the G term is negative, compounds that have a larger free energy of activation
also have a smaller antimicrobial activity. With a positive sign to the coefficient on log P, more
lipophilic compounds have a higher antimicrobial activity.
Question 9
The Hansch equation including log P and (log P)2 is shown below.
log BR 7.33 log P 0.64(log P ) 2 17.79
n = 7, r = 0.96
The value for log P can be determined by setting the first derivative of the Hansch equation with
respect to log P to 0 and then solving for log P.
d log BR
7.33 1.28 log P
d log P
0 7.33 1.28 log P o
1.28 log P o 7.33
log P o 5.73
A plot of calculated log BR vs. log P (with the experimental data points) demonstrates the parabolic
nature of the relationship of activity and log P.
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68
It is unlikely that electronics or sterics play a very significant role in the activity of this series of
compounds. The correlation coefficient for the Hansch equation is 0.96, and r2 is 0.93. The
parameters in this equation account for 93% of the variability in the data set. That does not leave much
room for the importance of electronic and/or steric parameters.
Question 10
While predicting activity for any series of compounds can be a significant challenge, if the compounds
are very similar in structure, then the prediction is greatly simplified. To be able to predict activity
trends for a diverse grouping of structures is a far harder task. The fact that CoMFA models can
accommodate compounds with dissimilar structures and determine trends in biological activity attests
to the power of the CoMFA method.
Question 11
Questions 7 (log P), 8 (G and log P), and 9 (log P and (log P)2) all generated new Hansch equations.
The plots of calculated vs. experimental activities for the three questions are shown below. In all
cases, the trendlines for the calculated vs. experimental data plots have a correlation coefficient that is
equivalent to the fit of the Hansch equation. This method, plotting calculated vs. experimental
activities and determining the correlation of the best-fit line, is how the fit of the Hansch equation is
determined.
log BC 0.54 log P 0.12
n = 8, r = 0.95
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69
log AA 0.28G 0.35 log P 4.75
n = 9, r = 0.90
log BR 7.33 log P 0.64(log P ) 2 17.79
n = 7, r = 0.96
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70
Question 12
A Craig Plot helps ensure that R-groups with a variety of properties are included in the training set of a
Hansch analysis. Craig Plots work well for Hammett (electronics) and Hansch (lipophilicity)
constants. Analogues with R-groups that reside in each of the four quadrants of the Craig Plot are
readily available.
A Craig Plot for Hansch (lipophilicity) and Taft (sterics) is not as straightforward. The two parameters
are not independent. Groups that provide high steric bulk tend to be more lipophilic. Therefore, they
do not scatter among the four quadrants of a Craig Plot. Performing a Hansch analysis with parameters
for both lipophilicity and sterics is difficult to accomplish meaningfully. Very careful attention must be
paid to the training set selection.
Question 13
The pKa value is an electronic parameter in the sense that it measures how easily a structure can accept
electron density from the breaking of a C-H bond. Stronger acids (lower pKa values) accept electron
density well, while weaker acids (higher pKa values) accept electron density poorly.
The pKa value is also lipophilicity parameter since on one side of the acid-base equilibrium the
compound will be neutral (i.e. more lipophilic) and on the other side it will be charged (i.e. less
lipophilic). Most commonly, acids (HCl) are neutral and their conjugate bases are anions (Cl). Other
charge possibilities can and do occur. Rarely, both an acid and conjugate base may have a charge, such
as with bicarbonate (HCO3) and carbonate (CO32). These are exceptions. Since the lipophilicity of
the species will change dramatically with the charge state of the structure, pKa has a huge influence on
lipophilicity. Indeed, this is the reason that the partition coefficient (P) has been elaborated to the
distribution coefficient (D) with accommodation of a pKa term.
Therefore, while pKa may be a common parameter in Hansch analyses, it is not as pure of a molecular
property term as the Hammett or Hansch constant.
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71
Question 14
Nitrogen mustards are DNA alkylating agents (Chapter 6). These are toxic compounds. It is therefore
no great surprise that the Hansch equation for biological activity is nearly identical to the Hansch
equation for toxicity. Finding a compound with a meaningful difference between efficacy and toxicity
would be a challenge.
The only room for hope is in the correlation coefficients. The Hansch equation for activity has a
somewhat lower correlation coefficient. There may be third property (sterics?) that is tied to activity
but not toxicity. Through this third parameter, a potent and safe analogue may be developed.
Question 15
This question is just like the Sample Calculation in the section on the Taft parameter except it is a
comparison for ethyl formate and ethyl propionate instead of ethyl formate and ethyl acetate. The set
up of the calculation is identical. It begins with Equation 12.17.
Es(R) log k R log k CH 3 log
kR
k CH 3
(12.17)
We already know that ethyl formate hydrolyzes 17.4 times faster than ethyl acetate. If we can calculate
how much faster ethyl acetate is than ethyl propionate, we can multiple the two factors together and
relate the rate of hydrolysis of ethyl formate to ethyl propionate.
Es(Er) log k Et log k CH3 log
0.07 log
k Et
k CH3
(12.17)
k Et
k CH 3
k Et
10 0.07 0.85
k CH 3
k CH 3
k Et
1.17
If ethyl formate hydrolyzes 17.4 times faster than ethyl acetate and ethyl acetate hydrolyzes 1.17 times
faster than ethyl propionate, the ethyl formate hydrolyzes 20.4 (17.41.17) times faster than ethyl
propionate.
Chapter 13
Question 1
First, one assumption needs to be made clear the product has an e.e. of 100%. With this assumption
one can then state that the product does not contain any of the undesired enantiomer.
In order to solve this question, one must remember that the starting material was racemic half one
enantiomer and half the other enantiomer. Although Scheme 13.3 starts with 67.1 g of material, the
math is simpler if we start with 100 g. So, in the 100 g of starting material, 50 g are the desired
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72
enantiomer, and 50 g are the other enantiomer. The resolution affords 39 g (39%) of the desired
enantiomer. Therefore, the remaining material must contain 11 g (50 39) of the desired enantiomer
and 50 g of the undesired enantiomer. The e.e. of the remaining 61% of the starting material can be
readily calculated with Equation 13.1.
major minor
major minor
e.e. 100
(13.1)
50 11
64%
50 11
e.e. 100
Question 2
The first step in this problem is to determine the molecular formula and then molecular weight of all
the starting materials and the desired product. It will not hurt to also calculate the formula and
molecular weight of all the waste products and make sure the starting materials and products balance.
F
13.56
H
N
O
Me
C16H12FNO
253.27
Bu3Sn
OEt +
BuLi
H2O
13.a
C16H34OSn
361.15
C4H9Li
64.06
H2O
18.02
F
13.57
total starting materials

C36H57FLiNO3Sn
SnBu4
+ EtOH
+ LiOH
total products
C36H57FLiNO3Sn
N
Me
C18H14FNO
279.31
O
C16H36Sn
347.17
C2H5O
46.07
HLiO
23.95
Atom economy for the reaction can be quickly calculated with Equation 13.2.
279.31
279.31
100
40.1%
253.27 361.15 64.06 18.02
696.50
atom economy 100
Question 3
Parenteral drugs are administered by injection (see Chapter 3 for a review). This question is ultimately
about bioavailability. When a drug is injected, the entire dose (with all impurities) is placed in the
body. In contrast, impurities in an oral drug may never be absorbed from the digestive system.
Because the bioavailability of metals from the digestive system is typically well under 100%, drug
regulations allow higher levels of metal impurities in oral drugs than injectable drugs.
Question 4
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73
In a kinetic resolution, the enzyme acts upon two different substrates. One is preferred and the other is
not. As the resolution progresses, the rate of the reaction slows for two reasons. One, the
concentration of the substrate decreases over time. With a lower substrate concentration, the rate of
conversion slows. The Michaelis-Menten equation shown below (Equation 4.11) reflects the
dependence of the rate of conversion upon the substrate concentration.
V
Vmax [S]
K m [S]
(4.11)
Two, not only is the substrate concentration decreasing, but the concentration of the preferred substrate
accounts for the vast majority of the decrease early in the reaction. The two substrates have different
affinities for the enzyme. In other words, each substrate has its own Km value. Km of the preferred
substrate is lower (higher affinity) than the Km of the not preferred substrate. As the preferred substrate
is consumed, the enzyme more and more begins to act on the not preferred substrate. Since the rate of
conversion of the not preferred substrate is low, the observed overall rate of the reaction slows with
percent conversion.
Question 5
The seven methods fall under two larger categories: resolutions and asymmetric synthesis. Examples
of resolutions include (1) kinetic resolutions, (2) separations of diastereomeric salts, and (3) chiral
chromatography. Examples of asymmetric synthesis include (4) purchase of enantiomerically pure
materials, (5) use of a chiral auxiliary, (6) asymmetric catalysis, and (7) microbial processes.
The reaction associated with this question is depicted below. A key feature is that the synthesis begins
with a racemic material. This fact alone makes the reaction a resolution. It may then be
subcategorized as a kinetic resolution, diastereomeric salt separation, or application of chiral
chromatography. In the reaction, enzymes within a microbe (Candida antarctica) preferentially
perform a hydrolysis on one enantiomer over the other. This is a kinetic resolution.
F
F
13.b
36% yield
93% e.e.
(racemic)
13.c
Candida
antartica
O
O
N
PhO
OH
30o
HO2C
O
13.c
61% e.e
O
N
PhO
N
O
PhO
HO2C
O
Question 6
Maximizing atom economy is Principle #7 of green chemistry, but it is just one measure of
greenness. Although having a high atom economy does not necessarily merit the green label for a
synthesis, it does mean that the synthesis is possibly greener than routes with a lower atom economy.
Question 7
This question is an application of Equation 13.5.
E -factor
mass of total waste

mass of product
(13.5)
Erland Stevens
25
74
mass of total waste

250 tons
mass of total waste 25 250 tons 6,250 tons
This is probably an overestimation of the waste since corticoids have been widely used for decades.
Their synthesis and isolation have received much attention and are likely optimized well beyond the
typical pharmaceutical synthesis.
Question 8
This question is very similar to Question 2. The first step is to determine the molecule formula and
molecular weight of all the starting materials and the product.
O
O
OH
OH
O
O
OH
OH
O
salicylic acid
13.e
acetic
anhydride
O-acetyl
salicylic acid
13.f
acetic
acid
C7H6O3
138.12
C4H6O3
102.09
C9H8O4
180.16
C2H4O2
60.05
180.16
75.0%
138.12 102.09
atom economy 100
Question 9
Calculating the E-factor of the reaction requires the masses of each reagent or solvent used. If the
volume is provided for a reagent, the density of the material must be used to convert volume to mass.
All masses are reported in grams to keep the conversions to a minimum in the final calculation.
Reagent name
Density (g/mL)
Amount used
Mass used
n/a
100 g
100 g
Acetic anhydride
1.082
200 mL
216 g
Phosphoric acid (85%)
1.685
1 mL
2g
Water
1.000
2.8 L
2,800 g
Ethanol
0.789
700 mL
552 g
Salicylic acid (11.e)
E -factor
E -factor
mass of total waste

mass of product
(13.5)
100 216 2 2,800 552 120 3,550
30
120
120
Note that the mass of the product must be subtracted from the masses of the starting materials in the
calculation.
Erland Stevens
75
Question 10
Effective mass yield is very similar to E-factor with the exclusion of benign starting materials. All the
required masses have already been calculated in Equation 9. Both water and ethanol can be excluded
from the waste calculation.
mass of product
mass of non - benign reagents
(13.7)
120
120
100
38%
100 216 2
318
(13.7)
effective mass yield 100
effective mass yield 100
Question 11
Acetamidine and acetic acid are ideally suited to form strong hydrogen bonds that are often found in
cocrystals (see Figure 13.4). While the complex may be interpreted as a cocrystal, the pKa values of
acetamidine and acetic acid indicate that the two compounds will undergo a strong acid-base reaction.
The pKa difference is 6.7, well beyond the rule-of-thumb difference of 3 to qualify as a salt. The
crystal is almost certainly a salt, not a cocrystal.
H
N H
H
N H
O
Me
Me
N
H
O
Me
Me
H O
N H
H
cocrystal
interpretation
acid-base
interpretation
Question 12
Below is a version of Scheme 13.16 that reflects changing both reagents to their methyl analogues.
starting
materials
MW
(g/mol)
O
O
Cl
102
134
NaOMe
3 H2O
NH2OH
54
3 x 18
33
OMe
109
masses of
atoms in
reagents
CO2H
O
products
MW
(g/mol)
2 MeOH
NaCl
OH
60
2 x 32
58
CO2
2 H2O
NH3
44
2 x 18
17
Me
206
mass of atoms
in product
206
42%
134 102 109 54 (3 18) 33
modified Boots synthesis atom economy 100
Using methyl chloroacetate and sodium methoxide raises the atom economy to 42%, a boost of only
2%.
Erland Stevens
76
Question 13
The best solvent is the mixture of water and N,N-dimethylformamide. On first glance, the key factor
might be seen as solubility at 20 C. A lower solubility at low temperature translates to less lost
material in the recrystallization. The more important factor, however, is the percent change between
the high and low temperature values.
Solvent(s)
Solubility at 20 C
Solubility at 60 C
Percent
(g/L)
(g/L)
recovery
Water
10
55
18
Methanol
15
33
N,N-Dimethylformamide
10
20
50
Water + Methanol
20
100
20
Water + Acetone
175
350
50
Water + Acetonitrile
400
1200
33
Water + N,N-Dimethylformamide
35
510
Question 14
In a resolution, one of the diastereomers must precipitate from solution. Larger structures, including
those that include benzene rings, tend to have lower solubility than smaller structures. It is only
natural to use large acids/bases in resolutions to boost the molecular weight of the salt to induce
precipitation.
OH
HO2C
Me
(+)-lactic acid
13.15
Question 15
Below are the graphs in Figure 13.11.
OH
HO2C
Ph
(+)-mandelic acid
(enantiomer is
also available)
13.19
Erland Stevens
77
In the graph on the left, the product initially forms with a 60% e.e. With Equation 13.1, we know the
number for e.e. Rearrange the equation for major/minor, and that is the E-value of the enzyme. In this
case, the E-value is 4.
major minor
major minor
e.e. 100
(13.1)
major minor
major minor
60 100
major minor
major minor
0.6
0.6 major 0.6 minor major minor

1.6 minor 0.4 major
major
4
minor
In the graph on the right, the product initially forms with an 85% e.e. (It is hard to read precisely, but
the actual number is 87.5%.) Following the same logic as the previous calculation, the E-value works
out to be 12. (With 87.5% e.e., the E-value is 15.)
major minor
major minor
60 100
major minor
major minor
0.85
0.85 major 0.85 minor major minor
Erland Stevens

1.85 minor 0.15 major
major
12
minor
78

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