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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
xii Contents
11.7 Medicinal Importance of Garlic (Allium sativum) 275
11.8 Medicinal Importance of Ajwain (Trachyspermum ammi) 278
Questions 282
12. Experiments 283
13. Multiple-Choice Questions and Answers 305
Abbreviations 383
Bibliography 387
Index 393
1
Drug Discovery, Design and Development
1.1 INTRODUCTION
Proteins, carbohydrates, fats, vitamins, enzymes, etc., are the crucial chemical entities in
the human body. They form a complex network in all parts of the body. Variety of chemical
compositions lead to different biochemical reactions in human body. Every process in the
body is some sort of chemical conversion that leads to movements, thought processes,
feelings, pain, etc. The human body has also been provided with all the necessary chemical
components or precursors, various enzymes and neurotransmitters for the balanced and
proper functioning of all the life sustaining processes. Yet it so happens that some organs
or bioprocesses fail to function due to several exogenous or endogenous factors. Hence,
providing external aids, which we call “drugs” or “medicines”, is essential to restore the
normal functioning.
Drugs are essential chemical entities of synthetic or natural origin, which only modulate
the body functions. This explanation, however, does not qualify for the chemotherapeutic
agents used to treat parasitic infections, as they have no action on the human body, but,
are targeted to the infectious organism. The exogenous factors are of diverse nature, i.e.,
ranging from parasitic invasion to some chemical entities which tend to disrupt the normal
bodily functions. Hence, repairing becomes mandatory, if bodily repair mechanism does
not match the rate of damage. The endogenous factors may be responsible for defective
functioning of organs, any genetic or congenital factor, over- or underproduction of some
precursors which may lead to disorders. The classical examples of disorders due to
endogenous factors are the neurodegenerative disorders like Parkinsonism and Alzheimer’s
disease which arise due to the imbalance of acetylcholine and dopamine in the central
nervous systems (CNS). There is no absolute cure yet for these disorders. However, drugs
and therapies have been developed to prolong and improve the quality of life. Thus, drug
discovery can also be termed “patient-oriented science meant for improving the quality of
life by developing newer and safer therapeutic agents”.
More than 100 years ago, the mystery of why only certain molecules produced a specific
therapeutic response was rationalized by the ideas of Fischer and further elaborated by
Langley and Ehrlich that only certain cells contained receptor molecules that served as
hosts for the drugs. The resulting combination of a drug and receptor created a new super
4 Pharmaceutical Chemistry
study of reflex activity in the spinal cord. In 1820, Pelletier and Caventou isolated quinine
as sulfate salt from Cinchona bark.
In search of other bioactive compounds, some pharmaceutical companies were
established in Europe. The first one was established by Emmanuelle Merck (1794–1855) in
Darmstadt (Germany). Merck, first worked on the bulk isolation of alkaloids and other
chemical products. In 1848, his son isolated papaverine from mother liquors of the
crystallization of morphine (alkaloids). Revolution started in France in the early 19th
century with the advancement of organic chemistry, particularly the study of physiological
effects of certain alkaloids by F. Magendie (1783–1855) and C. Bernard (1813–1878).
Magendie was the first physiologist to use alkaloids for the treatment of diseases. In 1869,
chloral hydrate was used as hypnotic agent, previously prepared by chlorination of the
absolute alcohol. In 1950s, pharmacy began to undergo numerous transformations as a
consequence of the introduction of new pharmaceutical formulations such as gelatin
capsules (Mothes, 1883) or tablets (Brockedon, 1843). In 1853, Charles Pravaz invented the
hypodermic syringe, which has since then undergone numerous modifications. The last
quarter of the nineteenth century witnessed the preparation of solutions for injection—
which was further elaborated through volumes of clinical studies and perfectly established
injections—a new pharmaceutical formulation.
In broader sense, the history of innovation and discovery of drugs can be divided into
two great periods, the first period covers from 1820 to 1935 and accounts for developing
the methods of isolation and purification of natural products, obtaining new compounds
by chemical synthesis, and studying their physiological properties. During this period,
two generations of drugs were introduced: between 1820 and 1880, alkaloids and some
inorganic and organic products were introduced, and second-generation drugs such as
vaccines, serums, analgesics, antipyretics, hypnotics, or antiprotozoa were also introduced
(Fig. 1.2).
The birth of pharmaceutical (medicinal) chemistry was defined in this very period,
when Dr. Paul Ehrlich demonstrated that infectious diseases can be treated (and cured)
with drugs and postulated the receptor concept — one of the masterpieces of scientific
thought on drug research. The discovery of prontosil during 1932–1935 can be considered
the inflexion point of the second period.
The second period, the golden age of drug discovery, began in 1930 up to 1940, at the
dawn of World War-II. It started with the introduction of vitamins, hormones, sulfonamides,
antibiotics, and related derivatives. This generation of drugs revolutionized the structure
and practice of the pharmaceutical industry. It was followed by two more advancements
in terms of potency and selectivity. In the fourth generation (1960–1980), we can include
semi-synthetic antibiotics, CNS agents (psychopharmacological agents), autonomous
nervous systems agents (ǃ-blockers), and cardiovascular agents (diuretics, antihypertensive
agents). Presently, in the fifth generation, we include enzyme inhibitors [angiotensinconverting enzyme inhibitors, cyclooxygenase (COX) inhibitors, enzyme inhibitors against
virus and cancer], biotechnologically derived drugs, and so on.
Drug Discovery, Design and Development 5
Fig. 1.2: Generations of drugs
1.3 DRUG DISCOVERY: A HISTORICAL PERSPECTIVE
In early times, there was no possibility of understanding the biological origin of diseases.
Of necessity, progress in combating disease was incoherent and empirical. The use of
opium, ephedra, marijuana, alcohol, salicylic acid, digitalis, coca, quinine, and a host of
others still in use, long predates the rise of modern medicine.
In the early 16th century, the German medical doctor and natural scientist, Paracelsus,
original name was Phillip van Hohenheim which later changed to Philippus Theophrastus
Aureolus Bombastus van Hohenheim, formulated the “Doctrine of Signatures.” The
6 Pharmaceutical Chemistry
formulation of this doctrine was in perfect agreement with the dominating philosophies at
that time, and it had a major impact on the use of natural medicines. Even today, herbal
medical preparations are still widely used. Although “Doctrine of Signatures” is evidently
out from the conception of modern medicinal natural product research, the ideas of
Paracelsus prepared the foundation of rational drug discovery.
This productive idea hardly changed for the next half century and assisted in the
development of many useful drugs. However, a less fortunate corollary of this useful
picture was that it led to some limitation of creativity in drug design. The drug and its
receptor (whose molecular nature was unknown when the theory was formulated) were
each believed to be rigid molecules precrafted to fit into each other precisely. Today, it is
obvious that receptors are highly flexible trans-membrane glycoproteins which are
accessible from the cell surface that often comprise more than one drug compatible region.
The opposite extreme to lock and key is the zipper model. In this view, a docking
interaction takes place (much as the end of a zipper joins the talon piece) and, if adequate
complementarity is present, the two molecules progressively wrap around each other and
adapt to the steric needs of each other. A consequence of accepting this mutual adaptation
is that knowledge of the receptor ground state may not be particularly helpful as it adjusts
its confirmation to ligand binding. Thus, in many cases, one now tries to determine the
three-dimensional structure of the receptor-ligand complex. In those cases where X-ray
analysis remains elusive, modelling of the interactions involved is appropriate.
Previously, it was also noted that enzymes could be modulated for pharmacological
benefits. Nevertheless, enzymes catalyze biochemical reactions as they share many
characteristics with proteins as the glycoprotein components of receptors. Receptorligand interaction takes place with the receptor glycoproteins or with the interfaces
between the macromolecular subunits of di- or poly-component receptor complexes that
modify the confirmation and dynamics of these complexes. Thus, neither receptor agonists
nor antagonists directly interfere in chemical reactions as they are dissociated from the
structurally unchanged receptor recognition sites.
The reaction mechanism underlying the function of the vast majority of enzymes has
been elucidated in detail which is based on such mechanistic information. It has been
possible to design a variety of mechanism based enzyme inhibitors, notably, k
inactivators
cat
and transition state analogues which are frequently in therapeutic use. By now, the
investigators could inhibit enzyme action rather than facilitate it. Actually, diseases
frequently result from excessive enzymatic action wherein selective inhibition of these
enzymes qualifies the ligand of therapeutic use.
Much later, a number of other classes of receptors were explored, and also exploited as
therapeutically significant pharmacological targets. This heterogeneous group of receptors
comprises nuclear receptors operated by steroid hormones and other lipophilic biochemical
mediators — a broad range of membrane-ion channels, DNA or RNA, and a number of
other bio-structures of known and unknown functions.
Drug Discovery, Design and Development 7
Thus, drug discovery is an exceedingly complex and demanding venture. Investigators
must pursue multiple lines of investigation involving diverse disciplines, often with
conflicting goals, and integrate the data to achieve a balanced clinical candidate. The last
decade documented considerable observations focusing the optimization of absorption,
distribution, metabolism, excretion, and toxicity (ADME/Tox) properties (e.g.,
physicochemical, metabolic, toxicity) of compounds, in addition to pharmacology (e.g.,
efficacy, selectivity), to translate the drug in success. Christopher A. Lipinski has
commented: Drug-like is defined as those compounds that have sufficiently acceptable
ADME properties and sufficiently acceptable toxicity properties to survive through the
completion of human Phase I clinical trials.
Drug properties have always been a prominent component of the developmental phase,
after discovery, during which detailed studies are performed on formulation, stability,
pharmacokinetics (PK), metabolism, and toxicity. However, in recent years it has become
imperative to integrate drug properties into drug discovery research.
“Drug-like properties are intrinsic properties of the molecules and it is the responsibility
of the medicinal chemists to optimize not only the pharmacological properties but also
the drug-like properties of these molecules.” (Ronald T. Borchardt)
This integration enables optimization of leads for ADME/toxicity during the course of
drug discovery. Simultaneously, comprehensive optimization of in vivo pharmacology,
pharmacokinetics, and safety issues have been another important advances. Further,
recognition of properties that have a major effect on the performance of a drug leads to
extensive biological experiments. Low solubility, permeability, or stability in assay media
alters the biological data that is used to develop structure-activity relationships (SARs), a
key aspect of drug discovery. Bio-scientists use property data to optimize bioassays, carrier
and in vivo routes of administration. Thus, drug-like properties have become crucial for
discovery through biological research.
Consequently, there are several tools to deal with drug-like properties of new molecules.
First, the interactions of drug molecules with the in vivo barriers they encounter after oral
administration. In order to understand, which properties limit drug exposure to the
therapeutic target, each significant property of the drug is explored (Fig. 1.3) in terms of:
Fundamentals of each property.
Effects of each property on ADME/toxicity and biological experiments.
Structure-property relationship (SPR) case studies, to see how structure affects
properties.
Structure modification strategies, to guide property optimization.
Property method descriptions, for accurate measurement and application of data.
8 Pharmaceutical Chemistry
Property
fundamentals
Property
effects
Structure
property
relationship
Fig. 1.3: Quality property assays by practical understanding through different aspects
Discovery scientist
Structural
modication
strategies
Biological
assay
Lead
Candidate
Property
assay
Knowledge of these properties equips discovery scientists for increased effectiveness in
lead selection, optimization, and enhancement of discovery biology. Drug-like properties
are important characteristics of potential clinical candidates. Thus, the basic principle in
lead development and optimization is to eliminate any shortcoming of lead candidate by
structural modifications. In addition to ADME/toxicity, a number of other characteristics
must also be satisfactory, such as:
Free from mutagenesis
Free from Teratogenicity
Chemical stability
Synthetic or biological availability
Affordable cost
Worth to patent
Clinical efficacy
Solubility
Apt taste
Ability to formulate satisfactorily for administration
Free from idiosyncratic problems.
These challenges emphasize the key importance of researchers trained in interdisciplinary
medicinal chemistry, in drug discovery and developmental programmes.
1.4 DRUG DISCOVERY AND DEVELOPMENT PROCESSES
It is crucial to briefly review the process of drug discovery and development before
discussing the effect of properties of drug candidate on activity. New drug candidates are
found during the discovery stage (Fig. 1.4). After that they qualify for clinical development
and, if approved by the Food and Drug Administration (FDA), become drug products that
are used in patient therapy. However, the later stages impose stringent drug-like
requirements on the properties of active molecules. Thus, it is necessary to anticipate these
requirements during drug discovery and promote development of only those compounds
that have the highest chances of success.
Drug Discovery, Design and Development 9
Discovery
& Biological target-
ID & characterize
& Activity, selectivity
& Chemical
synthesis
& Property profiling
Fig. 1.4: Drug and developmental programmes and their major activities
Development
& Batch synthesis
& Analytical release
& Formulation &
stability
& Human efficacy
& Safety and PK
& Phase I - Human
safety and PK
& Phase II - Human
efficacy
& Phase III - Pivotal
large scale
efficacy
Clinical
application
& Manufacturing
& Patient therapy
& Side effect
monitoring
& Formulation
enhancement
Drug discovery is elaborated in greater detail in Fig. 1.5. In general, successive stages
involve increasing the specific way of study and more stringent advancement criteria. At
the initial stage the screening of active molecule is wide to explore diverse and specific
pharmacophore motifs. This leads to narrow down the possibilities to select a few lead
scaffolds. The exploration of structural activity relationships (SARs) is another cornerstone
of modern drug discovery, during the lead optimization stage. Finally, candidates for
development are subjected to in-depth studies to qualify/disqualify them for development.
1.4.1 Changing Emphasis on Properties in Discovery
At one time, binding to the active site of the target protein was a strong priority in
advancement of medicinal chemistry. Exploration of SAR by synthesis of analogues having
systematic modifications of the core structural scaffold has allowed optimization of binding
by orders of magnitude.
There is a strong emphasis on driving potency from the micromolar (ǍM) IC
high throughput screening (HTS) hits to the low nanomolar (nM) range of good clinical
candidates. However, the focus purely on activity may lead the researchers to a candidate
with properties which are worse than the original HTS hit. For example, if a candidate is
too polar to penetrate the blood brain barrier (BBB) and reach the intended CNS target, it
may have the issue of stability and rapidly cleared by first-pass metabolism, or solubility
to be absorbed from the intestine. These findings may hopelessly mislead a discovery
programme. Once nM activity is obtained, it is hard to go back and fix properties by
structural modifications because it may be necessary to modify the substructures that were
added in order to enhance the binding affinity as shown in Fig. 1.6.
range of
50
10 Pharmaceutical Chemistry
Fig. 1.5: Drug discovery stages: Goals and major activities
Good
drugs
Properties
Activity & property optimization
Activity optimization
Activity
Fig. 1.6: Changing strategy for drug candidates, from a focus on activity to balanced attention to activity and properties
Good
ligands
Primary focus on activity can yield compounds that are very effective as ligands for the
target protein, however the properties may be inadequate for the compounds to become
successful drugs. For example, increased lipophilicity can enhance target protein binding;
however, it also can reduce solubility and metabolic stability. Steady consideration to both
activity and properties (holistic approach) yields candidates that can result into promising
drugs. The balanced approach demonstrated in Fig. 1.7 is common in drug discovery
nowadays. Good activity and drug-like properties are complementary and both are
necessary for a good drug moiety. The most active or selective compound may not make
the best drug product because of property limitations that cause poor pharmacokinetic
Drug Discovery, Design and Development 11
(PK) performance or safety issues. A less potent compound with better properties may
produce a better in vivo therapeutic response and be a better drug species for patients.
Drug is tested like a sportsperson in the sport decathlon, where the candidate is tested
through many events/challenges and the combined performance determines success, not
being the best in individual events.
Activity
Properties
Fig. 1.7: Activity and properties of a pharmaceutical balance
The multitude of the challenges faced by the discovery scientists has been characterized
differently. One useful image is to characterize them as a series of hurdles that a compound
must qualify. Another useful analogy is juggling (Fig. 1.8). A diverse ensemble of crucial
elements must be simultaneously monitored and kept in balance in order to achieve better
drug candidate. Neglecting one element can cause the whole ensemble to crash.
Soluble
Novel
PK
Safe
Fig. 1.8: Success in drug discovery requires juggling diverse variables simultaneously
Stable
Selective
Active