Chapter 1
Introduction
Chapter Outline
1.1. Overview
1.2. Drugs Discovered without Rational Design
1.2.1. Medicinal Chemistry Folklore
1.2.2. Discovery of Penicillins
1.2.3. Discovery of Librium
1.2.4. Discovery of Drugs through Metabolism Studies
1.2.5. Discovery of Drugs through Clinical Observations 6
1.3. Overview of Modern Rational Drug Design
1.3.1. Overview of Drug Targets
1.3.2. Identification and Validation of
Targets for Drug Discovery
1.3.3. Alternatives to Target-Based Drug Discovery
1.3.4. Lead Discovery
1.3.5. Lead Modification (Lead Optimization)
1.1. OVERVIEW
Medicinal chemistry is the science that deals with the discov-
ery and design of new therapeutic chemicals or biochemicals
and their development into useful medicines. Medicines are
the substances used to treat diseases. Drugs are the mole-
cules used as medicines or as components in medicines to
diagnose, cure, mitigate, treat, or prevent disease.[1] Medici-
nal chemistry may involve isolation of compounds from
nature or the synthesis of new molecules; investigations
of the relationships between the structure of natural and/or
synthetic compounds and their biological activities; elucida-
tions of their interactions with receptors of various kinds,
including enzymes and DNA; the determination of their
absorption, transport, and distribution properties; studies of
the metabolic transformations of these chemicals into other
chemicals, their excretion and toxicity. Modern methods for
the discovery of new drugs have evolved immensely since
the 1960s, in parallel with phenomenal advances in organic
chemistry, analytical chemistry, physical chemistry, bio-
chemistry, pharmacology, molecular biology, and medicine.
For example, genomics,[2] the investigations of an organism’s
genome (all of the organism’s genes) to identify important
target genes and gene products (proteins expressed by the
genes) and proteomics, the characterization of new proteins,
or the abundance of proteins, in the organism’s proteome (all
of the proteins expressed by the genome)[3] to determine their
structure and/or function, often by comparison with known
The Organic Chemistry of Drug Design and Drug Action. http://dx.doi.org/10.1016/B978-0-12-382030-3.00001-5
Copyright © 2014 Elsevier Inc. All rights reserved.
1 1.3.5.1. Potency 12
2 1.3.5.2. Selectivity 12
2 1.3.5.3. Absorption, Distribution, Metabolism, and
3 Excretion (ADME) 13
4 1.3.5.4. Intellectual Property Position 13
5 1.3.6. Drug Development 13
1.3.6.1. Preclinical Development 13
7 1.3.6.2. Clinical Development (Human Clinical
7 Trials)14
1.3.6.3. Regulatory Approval to Market the Drug 14
9 1.4. Epilogue 14
10 1.5. General References 15
11 1.6. Problems 16
12 References 16
proteins, have become i­ncreasingly important approaches to
identify new drug targets.
Today, harnessing modern tools to conduct rational drug
design is pursued intensely in the laboratories of pharmaceu-
tical and biotech industries as well as in academic institutions
and research institutes. Chemistry, especially organic chem-
istry, is at the heart of these endeavors, from the application
of physical principles to influence where a drug will go in the
body and how long it will remain there, to the understanding
of what the body does to the drug to eliminate it from the sys-
tem, to the synthetic organic processes used to prepare a new
compound for testing, first in small quantities (milligrams)
and ultimately, if successful, on multikilogram scale.
First, however, it needs to be noted that drugs are not
generally discovered. What is more likely discovered is
known as a lead compound (or lead). The lead is a proto-
type compound that has a number of attractive character-
istics, including the desired biological or pharmacological
activity, but may have other undesirable characteristics, for
example, high toxicity, other biological activities, absorp-
tion difficulties, insolubility, or metabolism problems. The
structure of the lead compound is, then, modified by syn-
thesis to amplify the desired activity and to minimize or
eliminate the unwanted properties to a point where a drug
candidate, a compound worthy of extensive biological and
pharmacological studies, is identified, and then a clinical
drug, a compound ready for clinical trials, is developed.
1
2 The Organic Chemistry of Drug Design and Drug Action

The chapters of this book describe many key facets of
modern rational drug discovery, together with the organic
chemistry that forms the basis for understanding them. To pro-
vide a preview of the later chapters and to help put the material
in context, this chapter provides a broad overview of modern
rational drug discovery with references to later chapters where
more detailed discussions can be found. Prior to launching into
an overview of modern rational drug discovery approaches, let
us first briefly take a look at some examples of drugs whose
discoveries relied on circumstances other than rational design,
that is, by happenstance or insightful observations.
1.2. DRUGS DISCOVERED WITHOUT
RATIONAL DESIGN
1.2.1. Medicinal Chemistry Folklore
Medicinal chemistry, in its crudest sense, has been practiced
for several thousand years. Man has searched for cures of
illnesses by chewing herbs, berries, roots, and barks. Some
of these early clinical trials were quite successful; however,
not until the last 100–150 years has knowledge of the active
constituents of these natural sources been known. The earli-
est written records of the Chinese, Indian, South American,
and Mediterranean cultures described the therapeutic effects
of various plant concoctions.[4–6] A Chinese health science
anthology called Nei Ching is thought to have been writ-
ten by the Yellow Emperor in the thirteenth century B.C.,
although some believe that it was backdated by the third
century compilers.[7] The Assyrians described on 660 clay
tablets 1000 medicinal plants used from 1900 to 400 B.C.
Two of the earliest medicines were described about
5100 years ago by the Chinese Emperor Shen Nung in his book
of herbs called Pen Ts’ao.[8] One of these is Ch’ang Shan,
the root Dichroa febrifuga, which was prescribed for fevers.
This plant contains alkaloids that are used in the treatment of
malaria today. Another plant called Ma Huang (now known as
Ephedra sinica) was used as a heart stimulant, a diaphoretic
agent (perspiration producer), and recommended for treatment
of asthma, hay fever, and nasal and chest congestion. It is now
known to contain two active constituents: ephedrine, a drug that
is used as a stimulant, appetite suppressant, decongestant, and
hypertensive agent, and pseudoephedrine, used as a nasal/sinus
decongestant and stimulant (pseudoephedrine hydrochloride
(1.1) is found in many over-the-counter nasal decongestants,
such as Sudafed). Ephedra, the extract from E. sinica, also is
used today (inadvisably) by some body builders and endurance
athletes because it promotes thermogenesis (the burning of fat)
by release of fatty acids from stored fat cells, leading to quicker
conversion of the fat into energy. It also tends to increase the
contractile strength of muscle fibers, which allows body build-
ers to work harder with heavier weights.
Theophrastus in the third century B.C. mentioned opium
poppy juice as an analgesic agent, and in the tenth century
A.D., Rhazes (Persia) introduced opium pills for coughs, men-
tal disorders, aches, and pains. The opium poppy, Papaver
somniferum, contains morphine (1.2), a potent analgesic agent,
and codeine (1.3), prescribed today as a cough suppressant. The
East Asians and the Greeks used henbane, which contains sco-
polamine (1.4, truth serum) as a sleep inducer. Inca mail run-
ners and silver miners in the high Andean mountains chewed
coca leaves (cocaine, 1.5) as a stimulant and euphoric. The anti-
hypertensive drug reserpine (1.6) was extracted by ancient Hin-
dus from the snake-like root of the Rauwolfia serpentina plant
and was used to treat hypertension, insomnia, and insanity.
Alexander of Tralles in the sixth century A.D. recommended
the autumn crocus (Colchicum autumnale) for relief of pain of
the joints, and it was used by Avrienna (eleventh century Per-
sia) and by Baron Anton von Störck (1763) for the treatment of
gout. Benjamin Franklin heard about this medicine and brought
it to America. The active principle in this plant is the alkaloid
colchicine (1.7), which is used today to treat gout.

CH3 H3C N
HO H N
O
H OH
.
HCl O O
OR'
H NHCH3
OR O
Pseudophedrine hydrochloride 1.2, Morphine (R = Rʹ = H) Scopolamine
1.1 1.3, Codeine (R = CH3, Rʹ = H) 1.4
OCH3
H3CO OCH3
H3CO N
O H H3CO
N H O
H3C N OCH3 H OCH3 O
O H O HN
H3COOC OCH3
OCH3
O O
OCH3
Cocaine Reserpine Colchicine
1.5 1.6 1.7
Chapter | 1 Introduction 3

FIGURE 1.1 Parody of drugs discovered without rational design.

In 1633, a monk named Calancha, who accompanied the refers to all of the cardiac glycosides, is still manufactured
Spanish conquistadors to Central and South America, intro- by extraction of foxglove and related plants.
duced one of the greatest herbal medicines to Europe upon
his return. The South American Indians would extract the O
cinchona bark and use it for chills and fevers; the Europe-
R O
ans used it for the same and for malaria. In 1820, the active
constituent was isolated and later determined to be qui- OH H OH
HO O O H
nine (1.8), an antimalarial drug, which also has antipyretic
(fever-reducing) and analgesic properties. H OH
O O O
H HO H
OH
Digitoxin (R = H) Digoxin (R = OH)
H 1.9 1.10
HO N
H3CO
1.2.2. Discovery of Penicillins
N In 1928, Alexander Fleming noticed a green mold growing
Quinine in a culture of Staphylococcus aureus, and where the two
1.8 had converged, the bacteria were lysed.[10] This led to the
discovery of penicillin, which was produced by the mold.
Modern therapeutics is considered to have begun with Actually, Fleming was not the first to make this observation;
an extract of the foxglove plant, which was cited by Welsh John Burdon-Sanderson had done so in 1870, ironically also
physicians in 1250, named by Fuchsius in 1542, and intro- at St. Mary’s Hospital in London, the same institution where
duced for the treatment of dropsy (now called edema) in Fleming made the rediscovery![11] Joseph Lister had treated
1785 by Withering.[5,9] The active constituents are second- a wounded patient with Penicillium, the organism later found
ary glycosides from Digitalis purpurea (the foxglove plant) to be the producer of penicillin (although the strains discov-
and Digitalis lanata, namely, digitoxin (1.9) and digoxin ered earlier than Fleming did not produce penicillin, but,
(1.10), respectively; both are important drugs for the treat- rather, another antibiotic, mycophenolic acid). After Fleming
ment of congestive heart failure. Today, digitalis, which observed this phenomenon, he tried many times to repeat it
4 The Organic Chemistry of Drug Design and Drug Action

without success; it was his colleague, Dr Ronald Hare,[12,13] For many years, there was a raging debate regarding the
who was able to reproduce the observation. It only occurred actual structure of penicillin (1.12),[17] but the correct struc-
the first time because a combination of unlikely events all took ture was elucidated in 1944 with an X-ray crystal structure
place simultaneously. Hare found that very special conditions by Dorothy Crowfoot Hodgkin (Oxford); the crystal structure
were required to produce the phenomenon initially observed was not published until after the war in 1949.[18] Several differ-
by Fleming. The culture dish inoculated by Fleming must ent penicillin analogs (R group varied) were isolated early on;
have become accidentally and simultaneously contaminated only two of these early analogs (1.12, R = PhOCH2, penicillin
with the mold spore. Instead of placing the dish in the refrig- V and 1.12, R = PhCH2, penicillin G) are still in use today.
erator or incubator when he went on vacation, as is normally
done, Fleming inadvertently left it on his lab bench. When he + + +
returned the following month, he noticed the lysed bacteria. 5 1 6 &+
Ordinarily, penicillin does not lyse these bacteria; it prevents 2 1 &+
them from developing, but it has no effect if added after the 2
&22+
bacteria have developed. However, while Fleming was on +
vacation (July–August), the weather was unseasonably cold, 3HQLFLOOLQ9 5 3K2&+
and this provided the particular temperature required for the 3HQLFLOOLQ* 5 &+3K
mold and the staphylococci to grow slowly and produce the 
lysis. Another extraordinary circumstance was that the partic-
ular strain of the mold on Fleming’s culture was a relatively
good penicillin producer, although most strains of that mold
(Penicillium) produce no penicillin at all. The mold presum-
1.2.3. Discovery of Librium
ably came from the laboratory just below Fleming’s where The first benzodiazepine tranquilizer drug, Librium
research on molds was going on at that time. (7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiaze-
Although Fleming suggested that penicillin could be pine 4-oxide; chlordiazepoxide HCl; 1.13), was discovered
useful as a topical antiseptic, he was not successful in serendipitously.[19]
producing penicillin in a form suitable to treat infections.
Nothing more was done until Sir Howard Florey at Oxford NHCH3. HCl
University reinvestigated the possibility of producing peni- N
cillin in a useful form. In 1940, he succeeded in producing
penicillin that could be administered topically and systemi- Cl N+
–
O
cally,[14] but the full extent of the value of penicillin was not
revealed until the late 1940s.[15] Two reasons for the delay
in the universal utilization of penicillin were the emer-
gence of the sulfonamide antibacterials (sulfa drugs, 1.11; Chlordiazepoxide HCl
see Chapter 5, Section 5.2.2.3) in 1935 and the outbreak of 1.13
World War II. The pharmacology, production, and clinical
application of penicillin were not revealed until after the Dr. Leo Sternbach at Roche was involved in a program
war to prevent the Germans from having access to this won- to synthesize a new class of tranquilizer drugs. He originally
der drug. Allied scientists, who were interrogating German set out to prepare a series of benzheptoxdiazines (1.14), but
scientists involved in chemotherapeutic research, were told when R1 was CH2NR2 and R2 was C6H5, it was found that
that the Germans thought the initial report of penicillin was the actual structure was that of a quinazoline 3-oxide (1.15).
made just for commercial reasons to compete with the sulfa However, none of these compounds gave any interesting
drugs. They did not take the report seriously. pharmacological results.

R1
H2N SO2NHR N N R1
O
X X N+ –
Sulfa drugs N O
1.11 Y R2 Y R2
1.14 1.15
The original mold was Penicillium notatum, a strain that
gave a relatively low yield of penicillin. It was replaced by The program was abandoned in 1955 in order for Stern-
Penicillium chrysogenum,[16] which had been cultured from bach to work on a different project. In 1957, during a general
a mold growing on a grapefruit in a market in Peoria, Illinois! laboratory cleanup, a vial containing what was thought to
Chapter | 1 Introduction 5

H
NHCH3
N CH2Cl N
..
CH3NH2 CH2Cl
N+ – N
Cl O Cl + O–

1.16

CH3NH2

NHCH3
N CH2NHCH3 N

N+ – .. CH2 Cl
Cl O N 1.13
Cl
OH

SCHEME 1.1 Mechanism of formation of Librium

be 1.15 (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5) was found
and, as a last effort, was submitted for pharmacological test-
ing. Unlike all of the other compounds submitted, this one
gave very promising results in six different tests used for
preliminary screening of tranquilizers. Further investigation
revealed that this compound was not a quinazoline 3-oxide,
but, rather, was the benzodiazepine 4-oxide (1.13), presum-
ably produced in an unexpected reaction of the corresponding
chloromethyl quinazoline 3-oxide (1.16) with methylamine
(Scheme 1.1). If this compound had not been found in the
laboratory cleanup, all of the negative pharmacological
results would have been reported for the quinazoline 3-oxide
class of compounds, and benzodiazepine 4-oxides may not
have been discovered for many years to come.
Penicillin V and Librium are two important drugs that
were discovered without a lead. However, once they were
identified, they then became lead compounds for second
generation analogs. There are now a myriad of penicillin-
derived antibacterials that have been synthesized as the
result of the structure elucidation of the earliest penicil-
lins. Valium (diazepam, 1.17) was synthesized at Roche
even before Librium was introduced onto the market; this
drug was derived from the lead compound, Librium, and is
almost 10 times more potent than the lead.
CH3
O CH3
N
1.2.4. Discovery of Drugs through
Metabolism Studies
During drug metabolism studies (Chapter 7), metabolites
(drug degradation products generated in vivo) that are
isolated are screened to determine if the activity observed
is derived from the drug candidate or from a metabolite.
For example, the anti-inflammatory drug sulindac (1.18;
Clinoril) is not the active agent; the metabolic reduction
product (1.19) is responsible for the activity.[20] The non-
sedating antihistamine terfenadine (1.20; Seldane) was
found to cause an abnormal heart rhythm in some users
who also were taking certain antifungal agents, which
were found to block the enzyme that metabolizes terfena-
dine. This caused a build-up of terfenadine, which led to
the abnormal heart rhythms (Chapter 7). Consequently,
Seldane was withdrawn from the market. However, a
metabolite of terfenadine, fexofenadine (1.21; Allegra),
was also found to be a nonsedating antihistamine, but
it can be metabolized even in the presence of antifun-
gal agents. This, then, is a safer drug and was approved
by the Food and Drug Administration (FDA) to replace
Seldane.
COOH COOH
F F
CH3

Cl N
O S

CH3 S
Diazepam Sulindac CH3
1.17 1.18 1.19
6 The Organic Chemistry of Drug Design and Drug Action

CH3
CH3 COOH
CH3 CH3
. HCl CH3 Ph HCl
Ph
HO N HO N
Ph OH Ph OH
Terfenadine HCl Fexofenadine HCl
1.20 1.21

1.2.5. Discovery of Drugs through Clinical
Observations
Sometimes a drug candidate during clinical trials will
exhibit more than one pharmacological activity, that is, it
may produce a side effect. This compound, then, can be
used as a lead (or, with luck, as a drug) for the secondary
activity. In 1947, an antihistamine, dimenhydrinate (1.22;
Dramamine) was tested at the allergy clinic at Johns Hop-
kins University and was found also to be effective in reliev-
ing a patient who suffered from car sickness; a further study
proved its effectiveness in the treatment of seasickness[21]
and airsickness.[22] It then became the most widely used
drug for the treatment of all forms of motion sickness.
O N
H EtO HN
CH3
Ph O N N
NMe2 • Cl
Ph N N
O
CH3
Dimenhydrinate
1.22
There are other popular examples of drugs derived from
clinical observations. Bupropion hydrochloride (1.23), an
antidepressant drug (Wellbutrin), was found to help patients
stop smoking and became the first drug marketed as a smoking
cessation aid (Zyban). The impotence drug sildenafil citrate
(1.24; Viagra) was designed for the treatment of angina and
hypertension by blocking the enzyme phosphodiesterase-5,
which hydrolyzes cyclic guanosine monophosphate (cGMP),
a vasodilator that allows increased blood flow.[23] In 1991,
sildenafil went into Phase I clinical trials for angina. In Phase
II clinical trials, it was not as effective against angina as Pfizer
had hoped, so it went back to Phase I clinical trials to see how
high of a dose could be tolerated. It was during that clinical
trial that the volunteers reported increased erectile function.
Given the weak activity against angina, it was an easy deci-
sion to try to determine its effectiveness as the first treatment
for erectile dysfunction. Sildenafil works by the mechanism
for which it was designed as an antianginal drug, except it
inhibits the phosphodiesterase in the penis (phosphodiester-
ase-5) as well as the one in the heart (Figure 1.2).
O CH3
N
O N
HN HCl O2S
HO
N
Cl N HO2C CO2H 2
CH3
Bupropion HCl Sildenafil citrate
1.23 1.24
Sexual stimulation causes release of nitric oxide in the
penis. Nitric oxide is a second messenger molecule that turns
on (pun intended) the enzyme guanylate cyclase, which con-
verts guanosine triphosphate to cGMP. The vasodilator cGMP

L-Arg NO
Nitric oxide
Synthase
Stimulates
Erection
Guanylate cyclase

GTP Smooth Increased

cGMP muscle blood
relaxation flow

GMP Vasoconstriction
PDE 5

Inhibits
Viagra
FIGURE 1.2 Mechanism of action of sildenafil (Viagra)
Chapter | 1 Introduction 7

relaxes the smooth muscle in the corpus cavernosum, allowing
blood to flow into the penis, thereby producing an erection.
However, phosphodiesterase-5 (PDE-5) hydrolyzes the cGMP,
which causes vasoconstriction and the outflow of blood from
the penis. Sildenafil inhibits this phosphodiesterase, preventing
the hydrolysis of cGMP and prolonging the vasodilation effect.
1.3. OVERVIEW OF MODERN RATIONAL
DRUG DESIGN
The two principal origins of modern pharmaceutical indus-
tries are apothecaries, which initiated wholesale production
of drugs in the mid-nineteenth century, and dye and chemi-
cal companies that were searching for medical applications
for their products in the late nineteenth century.[24] Merck
started as a small apothecary shop in Germany in 1668 and
started wholesale production of drugs in the 1840s. Other
drug companies, such as Schering, Hoffmann-La Roche,
Burroughs Wellcome, Abbott, Smith Kline, Eli Lilly, and
Squibb, also started as apothecaries in the nineteenth cen-
tury. Bayer, Hoechst, Ciba, Geigy, Sandoz, and Pfizer began
as dye and chemical manufacturers.
During the middle third of the twentieth century, anti-
biotics, such as sulfa drugs and penicillins (Section 1.2.2),
Drug Preclinical &
target
Lead Lead
clinical
Regulatory
discovery modification approval
selection development
FIGURE 1.3 Typical stages of modern rational drug discovery and
development
antihistamines, hormones, psychotropics, and vaccines
were invented or discovered. Death in infancy was cut by
50% and maternal death from infection during childbirth
decreased by 90%. Tuberculosis, diphtheria, and pneu-
monia could be cured for the first time in history. These
advances mark the beginning of the remarkable discoveries
made today, not only in the pharmaceutical industry but also
in academic and government laboratories.
Figure 1.3 shows the typical stages of modern ratio-
nal drug discovery and development. Below we present an
overview of each of these steps to provide context for the
concepts discussed in subsequent chapters. Among these
topics, the interactions of drugs with their targets, the ratio-
nale and approaches to lead discovery, and the strategies
underlying lead modification have a strong basis in physical
and mechanistic organic chemistry and, hence, will be the
central themes of subsequent chapters.
1.3.1. Overview of Drug Targets
The majority of drugs exert their effects through interac-
tions with specific macromolecules in the body. Many of
these macromolecular drug targets are proteins. You may
recall that proteins are long polymer chains of amino acid
residues that can loop and fold to produce grooves, cavi-
ties, and clefts that are ideal sites for interactions with
other large or small molecules (Figure 1.4). Other drugs
exert their effects by interacting with a different class of
macromolecules called nucleic acids, which consist of long
chains of nucleotide residues. Figure 1.5 shows the model

FIGURE 1.4 Small molecule drug (quinpirol) bound to its protein target (dopamine D3 receptor). The cartoon on the right shows how a protein, such as
the D3 receptor, spans the membrane of a cell. The D3 receptor in red depicts its conformation when the drug is bound. The D3 receptor in yellow depicts
its conformation when no drug is bound. “TM” designates a transmembrane domain of the protein. Note the significant differences between the red and
yellow regions on the intracellular side of the membrane, prompted by the binding of quinpirol from the extracellular side (Ligia Westrich, et al. Biochem.
Pharmacol. 2010, 79, 897–907.) On the right is a molecular representation of the fluid mosaic model of a biomembrane structure. From Singer, S. J.;
Nicolson, G L. Science. 1972, 175, 720. Reprinted with permission from AAAS.