Chimica Farmaceutica Introduzione 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. Corso di Laure in Biotecnologie Pagina 2 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 3 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 4 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 5 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 6 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 7 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 8 Corso di Laure in Biotecnologie Pagina 9 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 Corso di Laure in Biotecnologie Cyanic Acid Pagina 10 The 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 11 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 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 12 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, 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 13 Discovery 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 14 Corso di Laure in Biotecnologie Pagina 15 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 16 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 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 17 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 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 18 Synthesis of Aspirin Corso di Laure in Biotecnologie Pagina 19 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 cyclooxygenase enzymes was identified as the basis of its therapeutic activity. Corso di Laure in Biotecnologie Pagina 20 Aspirin 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 antiinflammatory 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 21 The 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 antiinflammatory, 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 24 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 25 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 “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 26 The 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 28 Further Readings Corso di Laure in Biotecnologie Pagina 29 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 30 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. Corso di Laure in Biotecnologie 31 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 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 32 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 so-called social drug like cannabis in this divide? What about nicotine, or alcohol? Corso di Laure in Biotecnologie Pagina 33 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. Corso di Laure in Biotecnologie Pagina 34 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. Corso di Laure in Biotecnologie Pagina 35 Corso di Laure in Biotecnologie Pagina 36 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 37 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 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 38 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 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 39
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