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Pharmaceutical Chemistry
Introduction
Book Corso di Laure in Biotecnologie Pagina 2
History
During more than 2,000 years, Hippocratic medical tradition weighed
on the development of a modern medicine and a renewed approach of
the treatment of diseases. The basis for the use of drugs remained
founded on empirical theories linked to the equilibrium of body’s
“humors” consisting in sanguine, melancholic, phlegmatic and choleric.
Health and disease were seen as a question of balance or imbalance
with foods and herbs classified according to their ability to affect
natural homeostasis.
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Why Medicines?
Before the 1800s, pharmacy remained an empiric science, guided by
traditional medicine, inherited from “Ancients.”
Numerous drugs, most of them being prepared with plant extracts, sometimes
efficacious, were available. But none of them could respond to a chemical
definition of what we call today a drug, except drugs coming from mineral
kingdom.
The technology of making drugs was crude at best: tinctures, poultices, soups,
and infusions were made with water- or alcohol-based extracts of freshly
ground or dried herbs or animal products such as bone, fat, or even pearls,
and sometimes from minerals best left in the ground
Corso di Laure in Biotecnologie Pagina 4
Toward a New Science
The 18th century concluded its progress in chemistry with an enthusiastic environment.
Joseph Priestley in the United Kingdom, Carl Wilhelm Scheele in Sweden, Antoine
Laurent de Lavoisier in France, gave a precise signification to the chemical reactivity
and promoted a large number of substances to the statute of chemical reagents. Scheele
and Priestley prepared and studied oxygen. Both of them discovered nitrogen as a
constituent of air, carbon monoxide, ammonia, and several other gases; manganese,
barium and chlorine; isolated glycerin and many acids, including tartaric, lactic, uric,
prussic, citric, and gallic. Lavoisier is generally considered as the founder of modern
chemistry as creating the oxygen theory of combustion. He should be known as one of
the most astonishing 18th century “men of the Enlightenment,” the founder of modern
scientific experimental methodology. By formulating the principle of the conservation of
mass, he gave a clear differentiation between elements and compounds, something so
important for pharmaceutical chemistry.
Corso di Laure in Biotecnologie Pagina 5
Toward Chemistry
Few years later, Antoine François de Fourcroy, Louis Nicolas
Vauquelin, Joseph Louis Proust, Jöns Jakob Berzelius, Louis-Joseph
Gay-Lussac, and Humphrey Davy introduced new concepts in
chemistry. Those scientists integrated the practical advancements of
a new generation of experimenters. All these industrial innovations
would have their own impact on other developments in industrial and
then medicinal chemistry At the turn of the 19th century, as the result
of a scientific approach, drugs are becoming an industrial item. Claude
Louis Berthollet began the industrial exploitation of chlorine (1785).
Nicolas Leblanc prepared sodium hydroxide (1789) and then, bleach
(1796). Davy performed electrolysis and distinguished between acids
and anhydrides. Louis Jacques Thénard prepared hydrogen peroxide
and Antoine Jérôme Balard discovered bromide (1826)
Corso di Laure in Biotecnologie Pagina 6
Chemistry
The growing of therapeutic resources was mainly due to the mastery of chemical or
physico-chemical principles proposed by Gay-Lussac and Justus Von Liebig. This
chemists’ generation, by realizing all these discoveries, established the compost of the
therapeutic discoveries of the 19th century. The constitution of chemistry as a
scientific discipline found a new turn few decades later by crossing the road of biology
which included revolutionary works of Claude Bernard, Rudolph Virchow, and Louis
Pasteur. Besides these fundamental sciences, physiology, biochemistry, or microbiology
were becoming natural tributaries of the outbreak of pharmacology. Thus, rational
treatments were about to be designed on the purpose of new knowledge in various
clinical or fundamental fields. After a period characterized by extraction and purification
from natural materials (mainly plants), drugs would be synthesized in chemical factories
or prepared through biotechnology (fermentation or gene technology) after a rational
research, design and development in research laboratories.
Corso di Laure in Biotecnologie Pagina 7
Organic Chemistry
Whereas the purpose was to isolate active molecules from plants
during the first half of the 19th century, the birth of organic chemistry
following charcoal and oil industries, progressively led chemists and
pharmacists toward organic synthesis performed in what would be
called “laboratory” a new concept created by this generation of
scientists. Even when those laboratories hosted discoveries like active
principles extracted from plants, progresses in drug compounding and
packaging made irreversible industrialization processes. At the same
time, the economical dimension of growing pharmaceutical industry
transformed drugs as strategic items, mainly when it could interfere
with military processes, for instance during colonial expeditions
Corso di Laure in Biotecnologie Pagina 8
Toward Medicinal Chemistry
The “modern” word “pharmacology” became more and more often used by physicians
after the works of François Magendie in France or Oscar Schmiedeberg in Germany.
Progressively a clear dichotomy took place between those two entities. Materia Medica
considered drugs with a static and conservative view as for their production and the
compounding of medicines. It was somewhere considered as the natural history of
drugs. At the contrary, pharmacology was embracing the creation of drugs through a
more dynamic point of view, studying drugs with respect of their site and mechanism of
action. At the same time, medicinal chemistry was becoming the application of chemical
research techniques to the synthesis of new pharmaceuticals. During the early stages of
medicinal chemistry development, chemists were primarily concerned with the isolation
of medicinal agents found in plants. Today, in this field they are also equally concerned
with the creation of new synthetic drug compounds. As a constant, medicinal chemistry
is almost always geared toward drug discovery and development.
Corso di Laure in Biotecnologie Pagina 9
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More Chemistry
A radical turn in the development of new chemicals occurred when charcoal and then oil
distillation offered so many opportunities. After the extract of paraffin, carbon derivatives
chemistry knew considerable developments with a lot of industrial consequences during the
second third of the century. The first organic molecules used for their therapeutic properties
had acyclic structures: chloroform was discovered in 1831 by three independently working
chemists: Eugene Soubeiran of France (1831), Justus Von Liebig of Germany, and Samuel
Guthrie of the United States (1832). Von Liebig taught chemistry through books like
Physiology (1840), and Organic Chemistry in its Application to Physiology and Pathology
(1842) and editing the journal that was to become the preeminent chemistry publication in
Europe: Annalen der Chemie und Pharmazie. Liebig and Friedrich Wöhler began in 1825
various studies over two substances that had apparently the same composition – cyanic
acid and fulminic acid – but very different characteristics. The silver compound of fulminic
acid, investigated by Liebig was explosive; whereas Wöhler’s silver cyanate was not. These
substances, called “isomers” by Berzelius, lead chemists to suspect that substances were
defined not simply by the number and kind of atoms in the molecule but also by the
arrangement of those atoms.
Fulminic Acid Cyanic Acid
Corso di Laure in Biotecnologie Pagina 11The First Synthesis
The most famous creation of an isomeric compound was Wöhler’s “accidental”
synthesis of urea (1828), when failing to prepare ammonium cyanate. For the
first time someone prepared an organic compound by the means of inorganic
ones. That “incident” made Wöhler saying: “I can no longer, so to speak,
hold my chemical water and must tell you that I can make urea without
needing a kidney, whether of man or dog; the ammonium salt of cyanic
acid is urea”. Liebig and Wöhler’s original objective was to interpret radicals
as organic chemical equivalents of inorganic atoms. It was an early step along
the path to structural chemistry. Organic chemistry precipitously entered the
medicinal arena in 1856 when the youngster William Perkin, in an unsuccessful
attempt to synthesize quinine, stumbled upon mauveine, the first synthetic dye,
leading to the development of many other synthetic dyes, which will give birth
few decades later to the first antiseptic and anti-infectious drugs..
Corso di Laure in Biotecnologie Pagina 12Medicinal Chemistry
Indeed, industrial world understood that some of these dyes could have therapeutic
effects. Synthetic dyes, and especially their medical “side effects” helped to put Germany
and Switzerland in the forefront of both organic chemistry and synthesized drugs.
The dye–drug connection began to be a very prolific way to discover drugs. After the first
developments in organic chemistry during the first half of the 19th century, the question
of the chemical origin of life was clearly put in the forefront of the scientific debate. Since
Wöhler’s works, it was clear that chemistry was a unique science, with the same rules
governing reactions kinetics and atomic, radical, or molecular arrangements. A
characteristic of the way to continue on discovery pathway was a beginning of scientific
cooperation meaning as well multidisciplinary approaches as more curiosity from
scientists taking here and there the knowledge necessary to understand natural or
experimental phenomena. As an example, Louis Pasteur, the French emblematic
physicist and chemist after beginning his career as a specialist in crystallography,
studied the impact of bacteria on stereo-chemical properties of tartaric acid crystals, and
after productive research on alcoholic and acetic fermentations, put the concept of
spontaneous generation to pieces. As bacteria could react on organic substances, he
presumed that they also could be active on living beings.
Corso di Laure in Biotecnologie Pagina 13The Medicine Concept
Besides conceptual progresses, the formal evolution in the concept of
medicines was based on the radical transformation of the nature of
medicines. One of the theorists of this trend, Charles Louis Cadet de
Gassicourt, reported in the inaugural issue of the Bulletin de
Pharmacie (1809) that the use of complex preparations had to be
withdrawn in favor of pure substances. Pharmacist and physicians
had, first, to classify drugs and their use. This trend was much more
convenient with pure substances. Between 1815 and 1820, the first
active principles were isolated from plants. At that time, a new era in
pharmaceutical chemistry opened. Hereafter, drug activity would not
depend on the quality of extracts or tinctures and their inherent
variability in active principles. The only variability acceptable in
therapeutics would be the patient himself.
Corso di Laure in Biotecnologie Pagina 14Discovery of Alcaloids
The first controversy is to know who discovered morphine. Jean-Francois Derosne, in
Paris, prepared a crude extract of opium (with alcohol and water), and obtained, after
potassium carbonate precipitation, what he called “sel de Derosne.” Derosne’s
alkaloidal fraction lacked narcotic properties and was probably largely made of
narcotine (also known as noscapine), perhaps mixed with meconic acid. This work,
has been presented at the Institute of France in 1804, but only published in 1814. It
describes the isolation of a compound, but did not report any animal or human
experiment. A young German apothecary from Paderborn (Germany), Friedrich
Sertürner did, in fact, begin publishing on opium in 1805, and claimed to have begun
work before a paper on opium by Derosne had appeared in 1804. This claim has been
interpreted to mean that Sertürner began work in 1803. However, Sertürner’s earlier
work fixated on acid constituents of opium. Thus, his 1806 paper is mainly concerned
with the constituent we now know as meconic acid. It was only in 1817 that he
unequivocally reported the isolation of pure morphine. He prepared it by extracting opium
with hot water and precipitating morphine with ammonia. He obtained colorless crystals,
poorly soluble in water, but soluble in acids and alcohol. He then established that the
crystals carried the pharmacological activity of opium. The name “morphine” has been
coined later. The discovery was received by great perplexity: morphine had an alkaline
reaction toward litmus paper. The scientific world was doubtful and Pierre Jean Robiquet
performed new experiments in order to check Sertürner results. For the first time a
substance extracted from a plant was not an acid!
Corso di Laure in Biotecnologie Pagina 15Corso di Laure in Biotecnologie Pagina 16
Morphine: Among the First Alcaloids
Gay-Lussac finally accepted the revolutionary idea that alkaline drugs
could be found in plants. All alkaline substances isolated in plants
would be given a name with the suffix “-ine ” (Wilhelm Meissner,
1818) in order to remind the basic reaction of all these drugs.
Morphine gained wide medical use in the beginning of the 1860s
during the American Civil War, but many injured soldiers returned from
the war as morphine addicts, victims of the “soldiers’ disease”. In
1874, English researcher, C. R. Alder Wright (Saint Mary’s Hospital,
London) first synthesized (diacetylmorphine) by boiling morphine
acetate over a stove.
Corso di Laure in Biotecnologie Pagina 17Heroin
Twenty years later, Heinrich Dreser working for the Bayer Company of
Elberfeld, Germany, found (erroneously) that diluting morphine with acetyls
produced a drug without the common morphine side effects. In 1895, Bayer
began the production of diacetylmorphine and coined the name “heroin” and
introduced it, commercially, after another three years. At the beginning of the
20th century, heroin addiction rose to alarming rates driving United Kingdom,
United States and France to ban opium and opiate drugs. During next 70
years, morphine will be almost completely withdrawn from medical use, before
its “rehabilitation” that came through the so-called Hospice movement, founded
in the United Kingdom in order to alleviate suffering of dying patients within
hospitals.
Candace Pert, together with Solomon Snyder (Johns Hopkins, Baltimore,
USA), first identified opioid receptors in the brain in 1972. In 1975 Hans
Kosterlitz and John Hughes (Aberdeen, UK) reported the existence of an
endogenous morphine-like substance and named it enkephalin (for “in the
head”). Enkephalins, endorphins, and dynorphins bind to specific receptor sites
in the brain.
Corso di Laure in Biotecnologie Pagina 18The Chemical Discovery of Aspirin
Another active principle soon extracted from plants was salicylic acid. Salicin,
extracted from the willow tree, has been launched in 1876 by a Scottish physician,
Thomas John McLogan.
It was in extensive competition with Cinchona bark and quinine and never became a
very popular treatment for fever or rheumatic symptoms.
The Italian chemist Raffaele Piria, after having isolated salicylaldehyde (1839) in
Spireae species, prepared salicylic acid from salicin.
This acid was easier to use and was an ideal step before future syntheses. Its
structure was closely related to benzoic acid, an effective preservative useful as an
intestinal antiseptic for instance in typhoid fever.
Acetylsalicylic acid has been first synthesized by Charles Frederic Gerhardt in 1853
and then, in a purer form, by Johann Kraut (1869).
Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by
Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest.
Corso di Laure in Biotecnologie Pagina 19Synthesis of Aspirin Corso di Laure in Biotecnologie Pagina 20
Aspirin as a Drug
During the 1880s and 1890s, physicians became intensely interested in the
possible adverse effects of fever on the human body and the use of antipyretics
became one of the hottest fields in therapeutic research.
It is likely that acetylsalicylic acid was synthesized under Arthur Eichengrün’s
direction and that it would not have been introduced in 1899 without his
intervention.
Dreser carried out comparative studies of aspirin and other salicylates to
demonstrate that the former was less noxious and more beneficial than the latter.
Bayer built his fortune upon this drug which received the name of “Aspirin” the
most familiar drug name. For the first time, an industrial group illustrated the close
relationship between chemistry and practical therapeutics. It was not until the late
1970s that aspirin’s ability to inhibit prostaglandins production by the cyclo-
oxygenase enzymes was identified as the basis of its therapeutic activity.
Corso di Laure in Biotecnologie Pagina 21Aspirin Pharmacological Mechanism of Action
Prostaglandins are known as end-products of the so-called arachidonic acid cascade.
Arachidonic acid is normally stored in membrane-bound phospholipids and released by the
action of phospholipases. Enzymatic conversion of released arachidonic acid into
biologically active derivatives proceeds through several routes. First, cyclooxygenase
converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins,
prostacyclin and thromboxanes are derived. Second, the production of the leukotrienes
from arachidonic acid is initiated by the action of 5-lipoxygenase producing leukotrienes
which are also believed to play an important pathophysiological role in allergic
bronchoconstriction of asthma.
Through pharmacological intervention in the arachidonic acid cascade various anti-
inflammatory agents have been developed.
These include aspirin-like drugs, which inhibit cyclooxygenase. Corticosteroids appear to
indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future
progress in this field is likely to produce drugs which antagonize arachidonic acid
derivatives or inhibit the enzymes involved in their synthesis with greater specificity.
The impact of aspirin administration at low dose for the prevention of stroke or coronary
attack resulted from its effect on enzymes regulating the production of prostaglandins.
Vane then assigned a major physiological function to the vascular endothelium which
became a pharmacological target for new drugs. He won Albert Lasker Prize in 1977 and
Nobel Prize in medicine and physiology in 1982
Corso di Laure in Biotecnologie Pagina 22The arachidonic acid cascade and its lipo-oxygenase branch
The arachidonic acid cascade and its lipo-oxygenase branch AA is metabolized by three major oxidative pathways: cyclooxygenase (COX), forming prostaglandins and related eicosanoids; lipoxygenase (LOX), forming leukotrienes and related compounds; CYP450, forming epoxides and 20-HETEs. Epoxyeicosatrienoic acids (EET)s are vasodilatory and anti-inflammatory, whereas 20-HETE antagonizes these effects of EETs. Soluble epoxide hydrolase (sEH) degrades EETs to their less bioactive corresponding dihydroxyeicosatrienoic acid (DHETs), thereby reducing beneficial effects of EETs. Inhibitors of sEH stabilize EETs, and prolong the duration of action of EETs, thus, enhancing the effects of reducing hypertension, inflammation, and pain
Aspirin Chemical Mechanism of Action Corso di Laure in Biotecnologie Pagina 25
The Discovery of Digitalic Compounds
In the second half of 18th century, William Withering, an English physician,
heard that the local population was able to cure dropsy using a complex
plant decoction. After having tested the various herbs on dropsy, digitalis leaf
remained the most active and probably contained a substance increasing the
ability of the weakened heart to improve pumping blood.
In 1775, Withering published a pamphlet in which he reported his discovery,
meticulously describing how the extract of the digitalis should be prepared,
and giving precise instructions on dosage, including warnings about side
effects and overdose from the experience learnt from 163 patients.
The only but not least problem was a dreadful continuous vomiting and
diarrhea during the treatment that was caused by the fact that the boundary
between the therapeutic dose and poisoning was exceedingly narrow.
It was therefore evident and absolutely necessary to purify the active
substance in order to fix the effective and non-toxic dosage.
After decades of works, Homolle and Quevenne, two Parisian pharmacists
obtained from foxglove leaves an amorphous substance they called
“digitaline,” keeping the “ine” terminology, as they were sure that it was an
alkaloid.
In fact it was a complex substance containing a specific sugar. It is not until
1867 that another French pharmacist, Nativelle was able to purify foxglove
leaves and to produce the effective substance in the form of white crystals
that he called “crystallized digitalin.”
Just a few years, later the German, Oswald Schmiedeberg, managed to
produce digitoxin (1875).
Corso di Laure in Biotecnologie Pagina 26Digitalis as a Cardiac Drug and Mechanism of Action
One hundred years later, explanation for the cardiotonic properties of digitalis, ouabain and
strophantin were given through molecular pharmacology experiments.
Skou studied in the early 1950s the action of local anesthetics. He thought that membrane protein
might be affected by local anesthetics. He therefore had the idea of looking at an enzyme which was
embedded in the membrane: ATPase, discovering that it was most active when exposed to the right
combination of sodium, potassium and magnesium ions. Skou left out the term “sodium-potassium
pump” from the title of his publication, continuing his studies on local anesthetics.
In 1958, Skou met Robert L. Post, who had been studying the pumping of sodium and potassium in
red blood cells recently discovered that three sodium ions were pumped out of the cell for every two
potassium ions pumped in, his research being made by the use of a substance called ouabain which
had recently been shown to inhibit the pump.
Conversations between Post and Skou about ATPase drove Skou to verify if ouabain inhibited the
pump. Indeed, it did inhibit the enzyme, thus establishing a link between the enzyme and the
sodium–potassium pump.
Skou received a Nobel Prize in Chemistry (1997). Julius C. Allen and Arnold Schwartz (Houston,
USA) then studied digitalis effect on cardiac contractility (positive inotropic effect), caused by the
drug’s highly specific interaction with Na+/K+-ATPase.
It has been established that partial inhibition of the ion pumping function of cardiac Na+/K+-ATPase
by digitalis glycosides led to a modest increase in intracellular Na+, which in turn, affected the
cardiac sarcolemmal Na+/Ca2+ exchanger, causing a significant increase in intracellular Ca2+ and in
the force contraction.
Corso di Laure in Biotecnologie Pagina 27The Introduction of the Term Receptor
As for giving a symbolic landmark to drugs history at the beginning of
the century, Paul Ehrlich (Institut für experimentelle Therapie,
Frankfurt) introduced, in 1900, the term “receptor.” The receptor
concept as such, was in fact developed in the context of immunology.
The drug receptor theory, in turn, would be later developed in Ehrlich’s
chemotherapy.
Corso di Laure in Biotecnologie Pagina 29Further Readings Corso di Laure in Biotecnologie Pagina 30
Medicinal Chemistry
A definition of medicinal chemistry was given by a IUPAC specialized
commission:
Medicinal chemistry concerns the discovery, the development, the
identification and the interpretation of the mode of action of biologically
active compounds at the molecular level.
Emphasis is put on drugs, but the interests of the medicinal chemist are
not restricted to drugs but include bioactive compounds in general.
Medicinal chemistry is also concerned with the study, identification, and
synthesis of the metabolic products of these drugs and related
compounds.
Corso di Laure in Biotecnologie 31Pharmaceutical Chemistry
Drugs – natural and synthetic alike – are chemicals used for medicinal
purposes. They interact with complex chemical systems of humans or
animals.
Medicinal chemistry is concerned with this interaction, focusing on the
organic and biochemical reactions of drug substances with their targets.
This is one aspect of drug chemistry.
Other important aspects are the synthesis and the analysis of drug
substances. The two latter aspects together are sometimes called
pharmaceutical chemistry , but the synthesis of drugs is considered by
some people – mainly chemists – to be part of medicinal chemistry,
denoting analytical aspects as pharmaceutical chemistry.
Corso di Laure in Biotecnologie 32MedChem Objectives
The objectives of medicinal chemistry are as easily formulated as they
are difficult to achieve: Find, develop and improve drug substances that
cure or alleviate diseases and understand the causative and
accompanying chemical processes .
Medicinal chemistry is an interdisciplinary science covering a particularly
wide domain situated at the interface of organic chemistry with life
sciences, such as biochemistry, pharmacology, molecular biology,
genetics, immunology, pharmacokinetics and toxicology on one side,
and chemistry-based disciplines such as physical chemistry,
crystallography, spectroscopy and computer-based techniques of
simulation, data analysis and data visualization on the other side
Corso di Laure in Biotecnologie 33What is a Drug
In medicinal chemistry, the chemist attempts to design and synthesize
a pharmaceutical agent that has a desired biological effect on the
human body or some other living system.
Such a compound could also be called a 'drug', but this is a word that
many scientists dislike because society views the term with suspicion.
With media headlines such as 'Drugs Menace’ or 'Drug Addiction
Sweeps City Streets’ this is hardly surprising.
However, it suggests that a distinction can be drawn between drugs
that are used in medicine and drugs that are abused.
Is this really true? Can we draw a neat line between 'good drugs' like
penicillin and 'bad drugs' like heroin?
If so, how do we define what is meant by a good or a bad drug in the
first place? Where would we place a so-called social drug like
cannabis in this divide? What about nicotine, or alcohol?
Corso di Laure in Biotecnologie Pagina 34Drug
• Drugs are compounds that interact with a biological system to
produce a biological response.
• No drug is totally safe. Drugs vary In the side effects they might
have.
• The dose level of a compound determines whether it will act as a
medicine or as a poison,
• The therapeutic index is a measure of a drug's beneficial effect at a
low dose versus its harmful effects at higher dose, A high
therapeutic Index Indicates a large safety margin between
beneticlal and toxic doses.
• The principle of selective toxicity means that useful drugs show
toxicity against foreign or abnormal cells but not against normal
host cells.
Corso di Laure in Biotecnologie Pagina 35Drugs → Formulation
Drugs are composed of drug substances (syn. active pharmaceutical
ingredients, APIs) and excipients (syn. ancillary substances). The
combination of both is the work of pharmaceutical technology (syn.
galenics) and denoted a formulation.
In 2007, the World Drug Index contained over 80,000 marketed and
development drug substances. In the United States, approximately
21,000 drug products were marketed in 2006; however, when duplicate
active ingredients, salt forms, supplements, vitamins, imaging agents,
etc. are removed, this number is reduced to only 1,357 unique drugs, of
which 1,204 are small molecule drugs and 166 are biologicals. In 2006 in
Germany, approximately 8,800 drugs in 11,200 formulations contained
approximately 2,400 APIs and 750 plant extracts. The WHO Essential
Medicines List held approximately 350 drug substances in 2007.
Corso di Laure in Biotecnologie Pagina 36Corso di Laure in Biotecnologie Pagina 37
Druggability
What makes a chemical “druggable”? Because of the versatility of their
molecular targets, there can be no universal characteristic of drug substances.
However since the general structure of the target organisms is identical,
generalizations as to drug substance structure are possible for biopharmacy.
For a chemical to be readily absorbed by the gut and distributed in the body, its
size, hydrophilicity/lipophilicity ratio, stability toward acid medium and
hydrolytical enzymes, etc. have to meet defined physicochemical criteria.
A careful analysis of reasons for drug attrition revealed that only 5% were
caused by pharmacokinetic difficulties whereas 46% were due to insufficient
efficacy and 33% to adverse reactions in animals or humans.
Since both wanted and unwanted effects are due to the biological activity, 79%
of drug candidates had unpredicted or wrongly predicted sum activities.
Predictions of toxicity from molecular features are very precarious.
Only rather general rules are for sure; such as avoidance of very reactive
functional groups, for example, aldehyde because of oxidative instability and
haptene nature; α,β-unsaturated carbonyl compounds and 2-halopyridines
because of their unspecific reactivity as electrophiles
Corso di Laure in Biotecnologie Pagina 38Drug Discovery/Invention?
Most drugs were discovered rather than developed. That is why a large number of drug
substances are natural products or derivatives thereof. It is a matter of debate if ethnic
medicines or nature still hold gems as yet undiscovered by pharmacy.
Synthetic substance collections (“libraries”) have been created through (automated)
organic chemistry. The very high number and diversity of natural and synthetic chemical
entities is faced with an equally growing number of potential reaction partners (targets)
from biochemical and pathophysiological research.
In virtual, biochemical and cell-based testing, compound selections are run against an
isolated or physiologically embedded target that may be involved in the disease process.
Compounds that exceed a certain threshold value in binding to the target or modulation
of some functional signal behind it, are called hits. If the identity and purity of the
compound and the assay result are confirmed in a multipoint activity determination, the
compound raises to the status of validated hit. From this one hopes to develop leads. A
lead is a compound or series of compounds with proven activity and selectivity in a
screen and fulfills some drug development criteria such as originality, patentability and
accessibility (by extraction or synthesis). Molecular variation hopefully tunes the
physicochemical parameters so that it becomes suitable for ADME.
Corso di Laure in Biotecnologie Pagina 39The Ideal Drug
The resulting optimized lead (preclinical candidate), if it displays no toxicity in cell and
animal models, becomes a clinical candidate. If this stands the tests of efficacy and
safety in humans and overcomes marketing hurdles, a new drug entity will enter the
treasure trove of pharmacy. The Box below will help to appreciate that activity is a
necessary but not sufficient quality of medicines. There is, of course, no ideal drug in
real world, but one has to find a relative optimum.
Corso di Laure in Biotecnologie Pagina 40Drug Discovery
1. The discovery step, consisting of the choice of the therapeutic target
(biochemical, cellular or in vivo model; see below) and the identification or
discovery and production of new active substances interacting with the
selected target.
2. The optimization step that deals with the improvement of an active
compound. The optimization process takes primarily into account the
increase in potency, selectivity and decrease in toxicity. Its characteristics
are the establishment of structure–activity relationships, ideally based on an
understanding of the molecular mode of action.
3. The development step, whose purpose is the continuation of the
improvement of the pharmacokinetic properties and the fine-tuning of the
pharmaceutic properties of active substances to render them suitable for
clinical use. This can consist, to name a few instances, in the preparation of
better-absorbed compounds, of sustained release formulations and of
water-soluble derivatives or in the elimination of properties related to the
patient’s compliance (irritation, painful injection, undesirable organoleptic
properties)
Corso di Laure in Biotecnologie Pagina 41Drug Discovery Optimization Algorithm Corso di Laure in Biotecnologie Pagina 42
Tuning of Pharmacologically Active Chemicals
An example of fine-tuning of pharmacologically active chemicals: Erythromycin 2'-
ethylsuccinate and clarithromycin are semisynthetic derivatives of the macrolide
antiinfective erythromycin. The small molecular change in the former leads to the
elimination of bitterness which is important as this class of drugs is often used in
pediatrics and administered as a syrup. In the latter, because hemiketal formation is no
longer possible (arrow), clarithromycin is stable in the acidic milieu of the stomach (pH 2)
Corso di Laure in Biotecnologie Pagina 43The Role of Medicinal Chemistry The main tasks of medicinal chemistry in the optimization and development steps consist in the optimization of the following characteristics: (a) Higher affinity for better activity so the dosage and nonspecific side effects will be as low as possible. There are no examples of drugs that are dosed
DRUG ACTIVITY PHASES
The way of a drug into the body, to its target(s), and out again can be
broken down into three mechanistically distinct phases, the second
and third being partly simultaneous. During drug development, all
three phases are investigated interdependently because structural
changes required for one phase must not abolish suitability in another
phase.
1.The pharmaceutical phase
2.The pharmacokinetic phase
3.The pharmacodynamic phase
Corso di Laure in Biotecnologie Pagina 45The pharmaceutical phase
Drug substances are applied orally (preferred mode) or parenterally
(e.g. by subcutaneous or intravenous injection, rectally, by inhalation).
A combination of the skills of medicinal chemists and pharmaceutical
technologists has to provide the drug candidate in suitable
formulations. For tablets, the drug substance needs to be crystalline
and not have a low melting point; for injections, it should be water
soluble, for example, as a salt. The required structural features must
be compatible with the pharmacological activity, of course.
Corso di Laure in Biotecnologie Pagina 46The pharmacokinetic phase
For this, medicinal chemists and biopharmacists work together to
design a compound that will have suitable ADME parameters.
Sufficient solubility in aqueous medium for absorption and blood
transport has to be combined with sufficient lipophilicity for passage
through cell membranes. If an active compound is too hydrophilic and
at the same time contains a carboxylic acid group, for instance,
conversion to a simple ester will facilitate absorption. Once in the
blood, unspecific esterases will catalyse hydrolysis to the active
carboxylic acid form. Such an ester is an instance of a prodrug.
Corso di Laure in Biotecnologie Pagina 47The pharmacokinetic phase
Drug substances should remain active and in the body neither too short nor too
long. For many drugs, a metabolic and/or excretion rate that enables “once a day”
dosage is aimed at. Sometimes this needs the identification of sites in the
molecule that will be metabolized quickly with concomitant loss of activity. The
vasodilator iloprost, for instance, was developed from the endogeneous mediator
prostacyclin that has very short half-life both in vivo and on the shelf. Modification
of several chemically and metabolically vulnerable positions yielded a stable and
active derivative – a highly sophisticated product of synthetic medicinal chemistry.
Prostacyclin and its synthetic analog, iloprost, that combines activity with sufficient
ex vivo and in vivo stability
Corso di Laure in Biotecnologie Pagina 48The pharmacokinetic phase
Vice versa, sometimes functionality is introduced for the acceleration of
biotransformation and excretion. Articaine is a local anesthetic of the anilide
type. Systemically, it interferes with heart rate – an unwelcome side effect in
dentistry. That is why articaine contains an additional ester group. Once in
the blood stream, this will be hydrolyzed quickly to an – in this case –
inactive carboxylic acid
Articaine, a common local anesthetic dentists use, and its inactive
metabolite that is formed off the scene of painful action.
Corso di Laure in Biotecnologie Pagina 49The pharmacodynamic phase
While pharmacokinetics investigates what the body does to the drug,
pharmacodynamics is concerned with what the drug does to the body.
Most scientists who consider themselves to be medicinal chemists will
be most comfortable with and interested in this phase. They will
cooperate with biochemists and pharmacologists to elucidate
mechanistic details of the interaction of the drug with its target(s).
Corso di Laure in Biotecnologie Pagina 50DRUG CLASSIFICATION SYSTEMS
Classification systems help with understanding what a drug actually
does at the molecular level (classification by target), and they are
indispensable for categorizing the large number of drug substances
(classification by clinical effect).
Corso di Laure in Biotecnologie Pagina 51Classification by target
Targets are molecular structures, chemically definable by at least a
molecular mass, that will undergo a specific interaction with chemicals
that we call drugs because they are administered to treat or diagnose
a disease. To be meaningful, the interaction has to have a connection
with the clinical effect(s). It is very challenging to prove this.
A clinically relevant target might consist not of a single biochemical
entity, but the simultaneous interference of a number of receptors.
Only this will give a net clinical effect that might be considered
beneficial. It is only by chance that the current in vitro screening
techniques will identify drugs that work through such targets
Corso di Laure in Biotecnologie Pagina 52Classification by target
The number of targets presently “used” is still open to discussion in
medicinal chemistry, but various approaches converge at a few hundred.
The number of potential targets, however, was estimated to be several
hundred thousand in view of the manifold protein complexes, splicing
variants and possible interventions with signaling pathways. The problem
with counting is mainly 2-fold: firstly, the identifi cation of the reaction
partners of drug substances in the body, and secondly, exactly what to
define and count as the target. A target definition derived from the net
effect rather than the direct chemical interaction will require input from
systems biology, a nascent research field that promises to affect the drug
discovery process significantly. At the other end of the scale of precision,
we can define some targets very precisely on the molecular level. For
example, we can say that dihydropyridines block the CaV1.2a splicing
variant in heart muscle cells of L-type high-voltage activated calcium
channels
Corso di Laure in Biotecnologie Pagina 53Classification by target
The actual depth of detail used to define the target is primarily
dependent on the amount of knowledge available about the target and
its interactions with a drug. If the target structure has already been
determined, it could still be that the molecular effect of the drug cannot
be fully described by the interactions with one target protein alone. For
example, antibacterial oxazolidinones interact with 23S-rRNA, tRNA
and two polypeptides, ultimately leading to inhibition of protein
synthesis. In this case, a description of the mechanism of action that
only includes interactions with the 23S-rRNA target would be too
narrowly defi ned. In particular, in situations in which the dynamic
actions of the drug substance stimulate, or inhibit, a biological process,
it is necessary to move away from the descriptions of single proteins,
receptors and so on and to view the entire signal chain as the target.
Corso di Laure in Biotecnologie Pagina 54Corso di Laure in Biotecnologie Pagina 55
Classification by Mechanisms of action
An effective drug target comprises a biochemical system rather than a
single molecule. Present target definitions are static. We know this to be
insufficient, but techniques to observe the dynamics of drug–target
interactions are just being created. Most importantly, we are not able to
gauge the interaction of the biochemical “ ripples ” that follow the drug’s
initial molecular effect. It has been pointed out that “two components are
important to the mechanism of action … The first component is the initial
mass-action-dependent interaction … The second component requires a
coupled biochemical event to create a transition away from mass-action
equilibrium” and “drug mechanisms that create transitions to a
nonequilibrium state will be more efficient.”
Although the term “mechanism of action” itself implies a classification
according to the dynamics of drug substance effects at the molecular level,
the dynamics of these interactions are only speculative models at present,
and so mechanism of action can currently only be used to describe static
targets.
Corso di Laure in Biotecnologie Pagina 56Classification by Mechanisms of action
All drugs somehow interfere with signal transduction, receptor signaling and
biochemical equilibria. For many drugs we know, and for most we suspect, that they
interact with more than one target. So there will be simultaneous changes in several
biochemical signals, and there will be feedback reactions of the pathways disturbed.
In most cases, the net result will not be linearly deducible from single effects. For
drug combinations, this is even more complicated. Awareness is also increasing of
the nonlinear correlation of molecular interactions and clinical effects. For example,
the importance of receptor–receptor interactions (receptor mosaics) was
summarized for G-protein-coupled receptors (GPCRs), resulting in the hypothesis
that cooperativity is important for the decoding of signals, including drug signals.
Greater knowledge of how drugs interact with the body (mechanisms of action, drug–
target interactions) has led to a reduction of established drug doses and inspired the
development of newer, highly specific drug substances with a known mechanism of
action. However, a preoccupation with the molecular details has resulted in a
tendency to focus only on this one aspect of the drug effects.
Corso di Laure in Biotecnologie Pagina 57Corso di Laure in Biotecnologie Pagina 58
Classification by Mechanisms of action
With all our efforts to understand the molecular basis of drug action,
we must not fall into the trap of reductionism. Indeed, the “ one-drug-
one-target ” hypothesis (perhaps even adding “ one disease,”
ignoring the complexity of medical diagnoses) may partly be
responsible for the relative dearth of new drug substances. For
antibacterial research, multitargeting is now considered to be
essential. More generally, in recent years the limits of the reductionist
approach in drug discovery have become painfully clear. Nobel
laureate Roald Hoffmann put it this way:
Chemistry reduced to its simplest terms, is not physics. Medicine is not
chemistry … knowledge of the specific physiological and eventually
molecular sequence of events does not help us understand what [a]
poet has to say to us
Corso di Laure in Biotecnologie Pagina 59Classification by Mechanisms of action Corso di Laure in Biotecnologie Pagina 60
Other classification systems
From a pharmaceutical standpoint there are many different criteria which
can be used to classify medications: type of formulation, the frequency
with which it is prescribed or recommended, price, refundibility,
prescription or nonprescription medication, etc. If a classification of the
APIs is undertaken, numerous possibilities are revealed, as well. At the
end of the 19th century, drug substances were classified the same as
other chemical entities; by nature of their primary elements, functional
moieties or organic substance class. Recently, the idea of classifying drug
substances strictly according to their chemical constitution or structure has
been revived. Recent databases attempt to gather and organize
information on existing or potential drug substances according to their
chemical structure and diversity. The objective is to create substance
“libraries,” which contain pertinent information about possible ligands for
new targets (e.g. an enzyme or receptor) of clinical interest and more
importantly, to understand the systematics of molecular recognition
(ligand–receptor).
Corso di Laure in Biotecnologie Pagina 61ATC Classification
The most commonly used classification system for drug substances is
the ATC system. It was introduced in 1976 by the Nordic Council on
Medicines as a method to carry out drug utilization studies throughout
Scandinavia. In 1981, the World Health Organization recommended
the use of the ATC classification for all global drug utilization studies
and in 1982 founded the WHO Collaborating Centre for Drugs
Statistics Methodology in Oslo to establish and develop the method.
Corso di Laure in Biotecnologie Pagina 62ATC Classification
The ATC system categorizes drug substances at five different levels according to
(1) the organ or system on which they act (Anatomy) (2) therapeutic and
pharmacological properties and (3) chemical properties. The first level is comprised
of the main anatomical groups, while the second level contains the
pharmacologically relevant therapeutic subgroup. The third level consists of the
pharmacological subgroup and the fourth the chemical subgroup. The fifth level
represents the chemical substance (the actual drug entity). Drugs with multiple
effects and different target organs can be found more than once within the system.
The antiinflammatory agent diclofenac, for instance, has three ATC numbers, one of
them being M01AB05. This key breaks down to: M01 (musculo-skeletal system;
antiinflammatory and antirheumatic agents, nonsteroids), M01AB (acetic acid
derivatives and related substances), 05 (diclofenac in M01AB). The two other keys
classify diclofenac as a topical agent and its use for inflammation of sensory organs
While ATC is better suited if the emphasis is on therapeutic use, the recently
proposed TCAT system puts the target chemistry first, suiting the medicinal
chemical approach.
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