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Medicinal Chemistry I IInd Module Introduction

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Medicinal Chemistry

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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 bodys humors consisting in sanguine, melancholic, phlegmatic and choleric. Health and disease were seen as a question of balance or imbalance with foods and herbs classied according to their ability to affect natural homeostasis.

Medicinal Chemistry

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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 denition 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 alcoholbased 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

Medicinal Chemistry

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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 signication 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 scientic 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.

Medicinal Chemistry

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Toward Chemistry
Few years later, Antoine Franois de Fourcroy, Louis Nicolas Vauquelin, Joseph Louis Proust, Jns Jakob Berzelius, LouisJoseph GayLussac, 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 scientic 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 Thnard prepared hydrogen peroxide and Antoine Jrme Balard discovered bromide (1826)
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Chemistry
The growing of therapeutic resources was mainly due to the mastery of chemical or physicochemical principles proposed by GayLussac 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 scientic 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 elds. After a period characterized by extraction and purication 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.
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Organic Chemistry
Whereas the purpose was to isolate active molecules from plants during the rst 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

Medicinal Chemistry

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Whereas the purpose was to isolate active molecules from plants during the rst 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

Medicinal Chemistry

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Toward Medicinal Chemistry


The modern word pharmacology became more and more often used by physicians after the works of Franois 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 eld 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.

Medicinal Chemistry

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Materia Medica

Medicinal Chemistry

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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 parafn, carbon derivatives chemistry knew considerable developments with a lot of industrial consequences during the second third of the century. The rst 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 Whler 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 Whlers silver cyanate was not. These substances, called isomers by Berzelius, lead chemists to suspect that substances were dened not simply by the number and kind of atoms in the molecule but also by the arrangement of those atoms.

Fulminic Acid
Medicinal Chemistry

Cyanic Acid
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The First Synthesis


The most famous creation of an isomeric compound was Whlers accidental synthesis of urea (1828), when failing to prepare ammonium cyanate. For the rst time someone prepared an organic compound by the means of inorganic ones. That incident made Whler 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 Whlers 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 rst synthetic dye, leading to the development of many other synthetic dyes, which will give birth few decades later to the rst antiseptic and antiinfectious drugs..
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Medicinal 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 dyedrug connection began to be a very prolic way to discover drugs. After the rst developments in organic chemistry during the rst half of the 19th century, the question of the chemical origin of life was clearly put in the forefront of the scientic debate. Since Whlers 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 scientic cooperation meaning as well muldisciplinary 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 stereochemical 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.

Medicinal Chemistry

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The 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, rst, to classify drugs and their use. This trend was much more convenient with pure substances. Between 1815 and 1820, the rst 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.
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Discovery of Alcaloids
The rst controversy is to know who discovered morphine. JeanFrancois 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. Derosnes 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 Sertrner 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 Sertrner began work in 1803. However, Sertrners earlier work xated 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 scientic world was doubtful and Pierre Jean Robiquet performed new experiments in order to check Sertrner results. For the rst time a substance extracted from a plant was not an acid!
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Medicinal Chemistry

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Morphine: Among the First Alcaloids


GayLussac nally 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 sufx 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 Marys Hospital, London) rst synthesized (diacetylmorphine) by boiling morphine acetate over a stove.
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Heroin
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 socalled 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), rst identied opioid receptors in the brain in 1972. In 1975 Hans Kosterlitz and John Hughes (Aberdeen, UK) reported the existence of an endogenous morphinelike substance and named it enkephalin (for in the head). Enkephalins, endorphins, and dynorphins bind to specic receptor sites in the brain.
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Heroin
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 socalled 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), rst identied opioid receptors in the brain in 1972. In 1975 Hans Kosterlitz and John Hughes (Aberdeen, UK) reported the existence of an endogenous morphinelike substance and named it enkephalin (for in the head). Enkephalins, endorphins, and dynorphins bind to specic receptor sites in the brain.
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The 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 rst 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.
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Synthesis of Aspirin

Medicinal Chemistry

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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 elds in therapeutic research. It is likely that acetylsalicylic acid was synthesized under Arthur Eichengrns 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 benecial than the latter. Bayer built his fortune upon this drug which received the name of Aspirin the most familiar drug name. For the rst time, an industrial group illustrated the close relationship between chemistry and practical therapeutics. It was not until the late 1970s that aspirins ability to inhibit prostaglandins production by the cyclooxygenase enzymes was identied as the basis of its therapeutic activity.
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Aspirin Pharmacological Mechanism of Action


Prostaglandins are known as endproducts of the socalled arachidonic acid cascade. Arachidonic acid is normally stored in membranebound 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 5lipoxygenase 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 inammatory agents have been developed. These include aspirinlike drugs, which inhibit cyclooxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this eld is likely to produce drugs which antagonize arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specicity. 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
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The arachidonic acid cascade and its lipo-oxygenase branch

Medicinal Chemistry

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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 20HETEs. Epoxyeicosatrienoic acids (EET)s are vasodilatory and antiinflammatory, whereas 20HETE 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

Medicinal Chemistry

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Aspirin Chemical Mechanism of Action

Medicinal Chemistry

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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 x the effective and nontoxic 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 specic 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).

Medicinal Chemistry

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Digitalis 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 sodiumpotassium 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 sodiumpotassium 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 drugs highly specic 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 signicant increase in intracellular Ca2+ and in the force contraction.

Medicinal Chemistry

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Medicinal Chemistry

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The Itroduction of the Term Receptor


As for giving a symbolic landmark to drugs history at the beginning of the century, Paul Ehrlich (Institut fr 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 Ehrlichs chemotherapy.

Medicinal Chemistry

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Further Readings

Medicinal Chemistry

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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.

Medicinal Chemistry

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Pharmaceutical 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.

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MedChem 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 chemistrybased disciplines such as physical chemistry, crystallography, spectroscopy and computerbased techniques of simulation, data analysis and data visualization on the other side
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What 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 socalled social drug like cannabis in this divide? What about nicotine, or alcohol?
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Drug
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.

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Drugs 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.

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Medicinal Chemistry

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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 dened physicochemical criteria. A careful analysis of reasons for drug attrition revealed that only 5% were caused by pharmacokinetic difculties whereas 46% were due to insufcient efcacy 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; ,unsaturated carbonyl compounds and 2halopyridines because of their unspecic reactivity as electrophiles
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Drug 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 cellbased 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 conrmed 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 fullls 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.

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The 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 efcacy 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 sufcient quality of medicines. There is, of course, no ideal drug in real world, but one has to nd a relative optimum.

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Drug Discovery
1. The discovery step, consisting of the choice of the therapeutic target (biochemical, cellular or in vivo model; see below) and the identication 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 structureactivity 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 netuning 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 betterabsorbed compounds, of sustained release formulations and of watersoluble derivatives or in the elimination of properties related to the patients compliance (irritation, painful injection, undesirable organoleptic properties)
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Drug Discovery Optimization Algorithm

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Tuning of Pharmacologically Active Chemicals

An example of netuning 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)
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The 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 afnity for better activity so the dosage and nonspecic side effects will be as low as possible. There are no examples of drugs that are dosed <10 mg/day that cause idiosyncratic adverse drug reactions. For drug substances that have to be given in higher doses the majority medicinal chemistry tries to nd active derivatives that will be metabolized in a safe way. This includes assaying for inhibition of or reaction with key enzymes of biotransformation, for example, oxi dases of the cytochrome type some of which are highly demanded by food constituents and xenobiotics including drug substances. Medicinal chemistry tries to prepare drugs that are not metabolized by bottleneck enzymic pathways. (b) Better selectivity may lead to a reduction of unwanted side effects. This entails that a sometimes very high number of other targets have to be assayed; for exam ple, an antidepressive serotonin reuptake inhibitor has to be tested against all subtypes of serotonin, adrenaline and dopamine receptors at least.

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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
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The 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.

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The pharmacokinetic phase


For this, medicinal chemists and biopharmacists work together to design a compound that will have suitable ADME parameters. Sufcient solubility in aqueous medium for absorption and blood transport has to be combined with sufcient 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, unspecic esterases will catalyse hydrolysis to the active carboxylic acid form. Such an ester is an instance of a prodrug.

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The 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 identication 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 halflife both in vivo and on the shelf. Modication 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 sufcient ex vivo and in vivo stability
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The 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.
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The 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).

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DRUG CLASSIFICATION SYSTEMS


Classication systems help with understanding what a drug actually does at the molecular level (classication by target), and they are indispensable for categorizing the large number of drug substances (classication by clinical effect).

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Classication by target
Targets are molecular structures, chemically denable by at least a molecular mass, that will undergo a specic 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 benecial. It is only by chance that the current in vitro screening techniques will identify drugs that work through such targets
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Classication 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 2fold: rstly, the identi cation of the reaction partners of drug substances in the body, and secondly, exactly what to dene and count as the target. A target denition derived from the net effect rather than the direct chemical interaction will require input from systems biology, a nascent research eld that promises to affect the drug discovery process signi cantly. At the other end of the scale of precision, we can dene 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 Ltype highvoltage activated calcium channels
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Classication by target
The actual depth of detail used to dene 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 23SrRNA, tRNA and two polypeptides, ultimately leading to inhibition of protein synthesis.29 In this case, a description of the mechanism of action that only includes interactions with the 23SrRNA target would be too narrowly de 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.

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Classication by Mechanisms of action


An effective drug target comprises a biochemical system rather than a single molecule. Present target denitions are static. We know this to be insufcient, but techniques to observe the dynamics of drugtarget interactions are just being created. Most importantly, we are not able to gauge the interaction of the biochemical ripples that follow the drugs initial molecular effect. It has been pointed out that two components are important to the mechanism of action The rst component is the initial massactiondependent interaction The second component requires a coupled biochemical event to create a transition away from massaction equilibrium and drug mechanisms that create transitions to a nonequilibrium state will be more ef cient. Although the term mechanism of action itself implies a classication 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.
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Classication 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 Gproteincoupled 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 specic 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.

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Classication 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 onedrug onetarget 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 specic physiological and eventually molecular sequence of events does not help us understand what [a] poet has to say to us

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Classication by Mechanisms of action

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Other classication 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 classication of the APIs is undertaken, numerous possibilities are revealed, as well. At the end of the 19th century, drug substances were classied 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 (ligandreceptor).
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ATC Classication
The most commonly used classication 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 classication 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.

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ATC Classication
The ATC system categorizes drug substances at ve different levels according to (1) the organ or system on which they act (Anatomy) (2) therapeutic and pharmacological properties and (3) chemical properties. The rst 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 fth 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 antiinammatory agent diclofenac, for instance, has three ATC numbers, one of them being M01AB05. This key breaks down to: M01 (musculoskeletal system; antiinammatory 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 inammation of sensory organs While ATC is better suited if the emphasis is on therapeutic use, the recently proposed TCAT system puts the target chemistry rst, suiting the medicinal chemical approach.
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