Nitroglycerin

Nitroglycerin - Nitroglycerin synthesis has been performed in 1844 by Antoine Jérôme Balard (Montpellier, France) who observed the collapse of animals few minutes after the administration of the drug. The vasodilatating effect of the drug was exploited by Ascani Sobrero (Torino, Italy) following work with Theophile-Jules Pelouze (1847) in Paris. Two years later, Konstantin Hering and Johann Friedrich Albers, developing the sublingual administration of nitroglycerin, observed the violent headache caused by the drug. Alfred Nobel, later founder of Nobel Prize, joined Pelouze in 1851 and recognized the potential of this yellow liquid with explosive interest. 55 He began manufacturing nitroglycerin in Sweden, overcoming handling problems with his patent detonator. 

Pictures of Nitroglycerin

Nitroglycerin Structural Formulae

Nitroglycerin 2,5 mg ER cap major Pharmaceuticals

Nobel suffered acutely from angina but refused what he considered as a chemical for a treatment. When the English physician Thomas Lauder Brunton succeeded to relieve severe recurrent angina pain in refractive patients except by bleeding, he realized that phlebotomy provided relief by lowering arterial blood pressure. This gave birth to the concept that reduced cardiac after load and work were benefi cial. When administering amyl nitrite, a potent vasodilatator, by inhalation, 

Brunton noticed, in 1867, that coronary pain was transiently relieved within 30–60 s. 56 In 1876, William Murrell (Westminster Hospital London) proved that the action of nitroglycerin mimicked that of amyl nitrite, and he established the use of sublingual nitroglycerin for relief of the acute angina attack and as a prophylactic agent to be taken prior physical exercise. Almost a century later, research in the nitric oxide (NO) fi eld explaining the mode of action of nitroglycerin, has dramatically extended. In 1977, Ferid Murad (Houston, USA) discovered the release of NO from nitroglycerin and its action on vascular smooth muscle.Robert Furchgott ( Figure 1.11 ) and John Zawadski (New York, USA) recognized the importance of the endothelium in acetylcholine-induced vaso-relaxation (in 1980) and Louis Ignarro (Figure 1.11) and Salvador Moncada (London, UK) ( Figure 1.10 ) identifi ed endothelial-derived relaxing factor (EDRF) as NO (in 1987). 57 Today, glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of nitroglycerin and its established effi cacy make it the mainstay of angina pectoris relief.

The role of NO in cellular signaling has become one of the most rapidly growing areas in biology during the past two decades. As a gas and free radical with an unshared electron, NO participates in various biological processes. NO is formed from the amino acid l -arginine by a family of enzymes, the NO synthases, and plays a role in many physiological functions. Its formation in vascular endothelial cells, in response to chemical stimuli and to physical stimuli such as shear stress, maintains a vasodilator tone that is essential for the regulation of blood fl ow and pressure. NO also inhibits platelet aggregation and adhesion, inhibits leukocyte adhesion and modulates smooth muscle cell proliferation. NO is also synthesized in neurons of the central nervous system (CNS), where it acts as a neuromediator with many physiological functions, including the formation of memory, coordination between neuronal activity and blood fl ow, and modulation of pain. In the peripheral nervous system, NO is now known to be the mediator released by a widespread network of nerves.

Digitalis

Digitalis - 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 ( Figure 1.9 ). 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.

Digitalis purpurea Candy Mountain

Fleur Digitale abeille digitaline champs

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 fi x the effective and non-toxic dosage.

After decades of works, Augustin Eugène Homolle and Théodore 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,

Claude Adolphe Nativelle was able to purify foxglove leaves and to produce the effective substance in the form of white crystals 49 that he called “ crystallized digitalin. ” Just a few years, later the German, Oswald Schmiedeberg, managed to produce digitoxin (1875). 50 Shortly thereafter reports began to come in about other medicinal herbs which had the same effect on the heart as the foxglove products. Ethnopharmacy gave birth to ouabain, extracted by Albert Arnaud from Acocanthera roots and bark, and strophantin, extracted from Strophantus . Both of these drugs had previously been used by arrow hunters in Equatorial Africa. One hundred years later, explanation for the cardiotonic properties of digitalis, ouabain and strophantin were given through molecular pharmacology experiments. The story began when Jens Christian Skou (Aarhus, Denmark) ( Figure 1.54 ) 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. 51 Only then did he realize that this enzyme might have something to do with the active transport of sodium and potassium across the plasma membrane. 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 (Nashville, USA), who had been studying the pumping of sodium and potassium in red blood cells 52 recently discovered that three sodium ions were pumped out of the cell for every two potassium ions pumped in, 53 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 (the positive inotropic effect), caused by the drug’s highly specifi c interaction with Na /K -ATPase. It has been established that partial inhibition of the ion pumping function of cardiacNa /K -ATPase by digitalis glycosides led to a modest increase in intracellular Na , which in turn, affected the cardiac sarcolemmal Na /Ca 2 exchanger, causing a signifi cant increase in intracellular Ca 2 and in the force contraction.

New strategies for rheumatoid arthritis

New strategies for rheumatoid arthritis - Drug therapy for rheumatoid arthritis (RA), a chronic infl ammatory and destructive joint disease, rests on two bases: symptomatic treatment with NSAIDs, not interfering with the underlying immuno-infl ammatory and disease-modifying ntirheumatic drugs (DMARDs), “ modifying” the disease process. DMARDs are divided into small-molecule drugs and biological therapies. The initial approach to understanding the pathogenesis of RA and defi ning a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro . In a series of experiments using tissue taken from joints, Marc Feldmann and Ravinder Maini (Kennedy Institute, London) investigated the role of cytokines ( Figure 1.8 ), protein messenger molecules that drive infl ammation, and found that a number of pro-infl ammatory cytokines were indeed present in the infl amed joints.

Picture of the join with rheumatoid arthritis

Rheumatoid arthritis

These investigations suggested that neutralization of tumor necrosis factor-alpha (TNF- ) with antibodies significantly inhibited the generation of other pro-infl ammatory cytokines. Their fi rst clinical trial was performed in 1992 at Charing Cross Hospital and revealed rapid and dramatic improvement of rheumatoid disease activity with anti-TNF therapy. The blockade of a single cytokine, TNF- , had farreaching effects on multiple cytokines and thereby exerted signifi cant anti-infl ammatory and protective effects on cartilage and bone of joints. A chimeric anti-TNF- highaffi nity antibody was initially tested, with substantial and universal benefi t. Then, a randomized placebo-controlled double-blind trial supported the proposition that TNF- was implicated in the pathogenesis of RA and was thus a key therapeutic target. 46 Three TNF inhibitors have been approved since 1998 for the treatment of RA.

First was infliximab (Remicade®), a chimeric (human-murine) IgG1 anti-TNF- antibody, administered intravenously. It binds with high affi nity to soluble and membrane-bound TNF-thus inhibiting it. The two others are Etanercept (Enbrel®) and Adalimumab (Humira®) a recombinant humanized monoclonal anti-TNF- antibody administered subcutaneously. 47 Feldmann and Maini received the Albert Lasker award for their discovery in 2003.

Controversies over coxibs

Controversies over coxibs - Another cyclo-oxygenase isoform, so-called type 2 (COX-2) has been discovered in the early 1990s by Daniel Simmons and W. L. Xie,39 chemists at Brigham Young University in Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced,40 and he kept his notebook notarized as proof of his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating II. Two Hundred Years of Drug Discoveries infl ammation.41 Besides the constitutive COX-1, participating to stomach protection and renal artery vasodilatation, this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs). this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs).42 COX-2 inhibitors were apparently safer from a digestive point of view but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI2 ), without coincidental inhibition of the platelet agonist vasoconstrictor thromboxane (TxA the platelet agonist vasoconstrictor thromboxane (TxA2 ). 

As PGI As PGI2 counters the cardiovascular effects of TxA2 and augments the response to thrombotic stimuli augments the response to thrombotic stimuliin vivo , this affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs. affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs.43

Among those controversies, the question whether selective COX-2 inhibitors are prothrombotic, or not, is not theoretical. Whereas aspirin and traditional NSAIDs inhibit both thromboxane A 2 and prostaglandin I2 , the coxibs leave thromboxane A thromboxane A 2 generation unaffected, refl ecting the absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque.44 Clinical observations and studies found that taking common NSAIDs was linked to a lower risk of certain cancers. 

When celecoxib was approved for familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition.

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chen found that taking common NSAIDs was linked to a lower risk of certain cancers. When celecoxib was approved for  familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition. 

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chenet al. (Columbus, USA) modifi ed the structure of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showed a substantial increase in apoptotic activity. of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showeda substantial increase in apoptotic activity.45 What a challenge for the future!

Aspirin and NSAIDs

Aspirin and NSAIDs - Another active principle soon extracted from plants was salicylic acid. Salicin, extracted from the willow tree, hasbeen launched in 1876 by a Scottish physician, Thomas John McLogan 31 . 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) 32 in Spireae species , prepared salicylic acid from salicin in Dumas’ laboratory in the Sorbonne, Paris. 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 fi rst synthesized by Charles Frederic Gerhardt in1853 33 and then, in a purer form, by Johann Kraut (1869).

Asetilsalsilat

Reaction aspirin and  salicylic cacid 

Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest. 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 fi elds in therapeutic research. The name of ArthurEichengrün, who performed the research and developmentbased pharmaceutical division where Felix Hoffmann worked, and Heinrich Dreser ( Figure 1.6 ) in charge of testing the drug with Kurt Witthauer and Julius Wohlgemuth are to be memorized for this historical discovery (1897). 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. 34 Dreser carried out comparative studies of aspirin and other salicylates to demonstrate that the former was less noxious and more benefi cial than the latter. 35 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 identifi ed as the basis of its therapeutic activity. 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, cyclo-oxygenase converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived. 36 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 broncho-constriction ofasthma. Through pharmacological intervention in the arachidonic acid cascade various anti-infl ammatory agents have been developed. These include aspirin-like drugs, which inhibit cyclo-oxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this fi eld is likely to produce drugs which antagonize arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specifi city. 37 Using an ingenious “ real time ” biological assay of bloodstream hormones irrigating an isolated organ, called the “ blood-bathed organ cascade, ” John Vane ( Figure 1.7 ) developed a system for highly sensitive monitoring of several mediators like angiotensin, bradykinin and prostaglandins and discovered prostacyclin, a potent platelet aggregation inhibitor. John Vane explained anti-infl ammatory drugs effects (among which aspirin remains a true leader) through their activity on cyclo-oxygenase and inhibition of prostacyclin and thromboxane production. 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.

Poppy extracts led to brain receptors

Poppy extracts led to brain receptors - The first controversy is to know who discovered morphine. Jean-Francois Derosne, 23 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. 24 It describes the isolation of a compound, but did not report any animal or human experiment. A young German apothecary from Paderborn (Grmany), Friedrich Sertürner did, in fact, begin publishingon opium in 1805, 25 and claimed to have begun work before a paper on opium by Derosne had appeared in 1804.

Opium  led to brain receptors

Opium poppy red led to brain receptors

This claim has been interpreted to mean that Sertürner began work in 1803. However, Sertürner’s earlier work fi xated on acid constituents of opium. Thus, his 1806 paper 26 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. 27 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 thefirst time a substance extracted from a plant was not an acid!Gay-Lussac fi 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 suffi x “ -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) fi rst synthesized (diacetylmorphine) by boiling morphine acetate over a stove. 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 ( Figure 1.4 ).

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.

The dawn of the organic chemistry crosses the birth of biology

The dawn of the organic chemistry crosses the birth of biology - A radical turn in the development of new chemicals occurred when charcoal and then oil distillation offered so many opportunities. After the extract of paraffi n, carbon derivatives chemistry knew considerable developments with a lot of industrial consequences during the second third of the century.

Chemistry

organic molecules

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), 9 Justus Von Liebig of Germany, 10 and Samuel Guthrie of the United States (1832). 11 Von Liebig taught chemistry through books like Organic Chemistry and its Application to Agriculture and Physiology (1840), and Organic Chemistry in its Application to Physiology and Pathology (1842) 12 and editing the journal that was to become the preeminent chemistry publication in Europe: Annalen der Chemie und Pharmazie. 

Liebig and Friedrich Wöhler ( Figure 1.3 ) 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 defi ned not simply by the number and kind of atoms in the molecule but also by the arrangement of those atoms. The most famous creation of an isomeric compound was Wöhler’s “ accidental ” synthesis of urea (1828), when failing to prepare ammonium cyanate. For the fi rst time someone prepared an organic compound by the means of inorganic ones. 13 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 ”. 14 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 fi rst synthetic dye, leading to the development of many other synthetic dyes, which willgive birth few decades later to the fi rst antiseptic and antiinfectious drugs. Indeed, industrial world understood that some of these dyes could have therapeutic effects.