I.Introduction 5 FIGURE 1.2 Frangois Magendic FIGURE 1.3 Friedrich Wohler some. trary.pharmacology was embracing the creation of drugs through a more dynamic point of view,studying drugs with nal that was to become the preeminent chemistry publica omng the applicati tion in Europe:Annalen der Chemie und Pharmazie.Liebig e.me and Friedrich Wohler(Figure 1.3)began in 1825 various maccuticals.During the early stages of medicinal chemis try development.chemists were primarily concerned with ferent characteristics.The silver compound of fulminic acid. Today,in investigated by Liebig was explosive:whereas Wohler's silver cyanate was not.These substances.called"isomers' chemistry is almost always geared toward drug discovery msts to and development. molecule but also by the arra ngement of those atoms The most famous creation of an isomeric compound B.The dawn of the organic chemistry was Wohler's"accidental"synthesis of urea(1828).when crosses the birth of biology d by he first tim A radical turn in the developmer of new chemicals made Wohler saying occurred when charcoal and then oil distillation offered so can no longer.so to speak.hold my chemical water and many opportunities.After the extract of paraffin,carbor must tell you that I can make urea without needing a kid chemistry knew consid ey.whet ,m or amm the centur The molecules used for their thera to inte et radicals as organic chemicale uivalents of inor peutic properties had acyclic structures:chloroform was ganic atoms.It was an early step along the path to struc discovered in 1831 by three independently working chem ural chemistry.Organic hemistry precipitously ce(1831) ugh hooks like Organic Chemistry and its Application to Agriculture and the development of many other synthetic dyes.which will
I. Introduction 5 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 fi 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. B . 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. The fi 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), 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 will FIGURE 1.2 François Magendie . FIGURE 1.3 Friedrich Wöhler . Ch01-P374194.indd 5 h01-P374194.indd 5 5/29/2008 5:41:56 PM /29/2008 5:41:56 PM
■6 CHAPTER I A History of Drug Discovery give birth few decades later to the first antiseptic and anti- BOX 1.1 Alkaloids infctouisdrues.lncdcedindtstialworidundcrtoodthal some of these nd gide effects"helped to put Germany and Switzerland in the forefront of both organic chemistry and synthesized drugs. the physician.in the traditional Ip uanha ()The The dye-drug conne ction began to be a very prolific way yea ph Bie hayme Caventou tion of the chemical origin of life was clearly ton.the drug eing morand more popul t was c clear that chemistry was a unique science,with the same rules gove hing re be extracted in the following years.Brucine ()caffeine as more curiosity from scier edge ne ry to und 88o but fot others such as colchicine it was well over emblematic physicist and chemist after beginning his entury before the stru ureswere finally Betweer as a specialist in crystallography,studied the impact of bac to a new relationshin bet medicine and these peutic tool in th onc an ace ut th rst ces.As bacteria could reac he aire des medicaments presumed that they also could be active on living beings. II.TWO HUNDRED YEARS OF DRUG DISCOVERIES de Derosne."Derosne's alkaloidal fraction lacked narcotic Besides conceptual progre es.the formal evolution in the concept of medicines was based on the radical transforma- own as tion of the nature of medicines.One of the theorists of this rend, e(ed in n in fa tion of a compound,but did not report any animal or human periment Sertumet did in fict in ublish pegin publis on op ium hy De that time ra in p Hereafter.drug activity would not depend on the quality of extracts or tincture sand their inherent variability in active onacid o opium. ted the isolation of pure morphine.He prepared it by extracting opium with hot water and precipitating morphine A.Pain killers:best-sellers and a.H po controversies (Box lI) e shed th 1.Poppy extracts led to brain receplors The firs after potassium carbonate precipitation,what he called"sel first time a substance extracted from a plant was not an acid
give 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. 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 prolifi c way to discover drugs. After the fi rst developments in organic chemistry during the fi rst half of the 19th century, the question of the chemical origin of life was clearly put in the forefront of the scientifi c 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 scientifi c 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. II. TWO HUNDRED YEARS OF DRUG DISCOVERIES 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, 15 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, fi rst, to classify drugs and their use. This trend was much more convenient with pure substances. Between 1815 and 1820, the fi 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. A. Pain killers: best-sellers and controversies (Box 1.1) 1 . Poppy extracts led to brain receptors The fi rst 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 (Germany), Friedrich Sertürner did, in fact, begin publishing on opium in 1805, 25 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 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 scientifi c world was doubtful and Pierre Jean Robiquet performed new experiments in order to check Sertürner results. For the fi rst time a substance extracted from a plant was not an acid! BOX 1.1 Alkaloids The fi rst alkaloid ever isolated, emetine, was found by Pierre Joseph Pelletier, the pharmacist, and François Magendie, the physician, in the traditional Ipecacuanha (1817). 16 The same year, Joseph Pelletier and Joseph Bienaymé Caventou extracted strychnine, a powerful neurostimulating agent, from Strychnos. Three years later (1820) they extracted quinine from various Cinchona species. 17 Pelletier and Caventou began an industrialization of quinine production, the drug being more and more popular as a tonic and antifever drug (before being recognized as a treatment of choice for malaria). An impressive cohort of alkaloids would be extracted in the following years. Brucine (1819), caffeine (1819), colchicine (1820), codeine (1832) 18 , atropine (1833) 19 , papaverine (1848) 20 were subsequently obtained. Coniine, extracted in 1826, was the fi rst alkaloid to have its structure established (Schiff, 1870) and to be synthesized (Ladenburg, 1889) 21 , but for others, such as colchicine, it was well over a century before the structures were fi nally elucidated. Between the years 1817 and 1850, a new generation of scientists gave rise to a new relationship between medicine and these new therapeutic tools. Nevertheless, in the fi rst two-thirds of the 19th century, pure alkaloids were seldom used, even if the fi rst medical textbook presenting alkaloids source of drugs the “ Formulaire des médicaments ” by François Magendie, where he tries to make more popular the use of morphine, and fought against old formulas 22 was published in 1822. 6 CHAPTER 1 A History of Drug Discovery Ch01-P374194.indd 6 h01-P374194.indd 6 5/29/2008 5:41:57 PM /29/2008 5:41:57 PM
II.Two Hundred Years of Drug Discoveries BAYER PHARMACEUTICAL PRODUCTS. a ASPIRIN 业 HEROIN FIGURE1.5 Soloman Snyder (left)and Candace Pert (right) HEROIN HYDROCHLORIDE Scientific studies of opioid neurotransmitters during the 1970s FARBENFABRIKEN OF ELBERFELD CO 40 Stune Street,New York, ing in the synthesis of multiple active peptides all of them haring the common N -terminal sequence of Tyr-Gly-Gly FIGURE 1.4 Aspirin and Heroin"co-advertising" (Met or Leu opioid m oids have been implicated in circuits involved in the cor trol of sensation.emotion.and affect and a role has been Gay-Lussac finally accepted the revolutionary idea that alka line drugs could be found in plants.All alkaline substances ascribed to them in addiction.not only to opiates such as plants be me with the morphine or heroin,but also to alcoh basic reaction of all these drugs ained wide 2.Aspirin and NSAIDs medical use in the beginning of the 1860s during the Another active principle soon extracted from plants was American Civil War.but many injured soldiers retumed salieylic acid.Salicin extracted from the willow tree,has 766 a Scottish physicia (San Mary's Hospital London)first synthesized (diacety 10n and nd n morphine)by boiling morphine acetate over a stove. lar treatment for fever or rheumatic symptoms.The ltalian Twenty years later.Heinrich Dreser working for the chemist Raffaele Piria,after having isolated salicylalde ld.Germany.fo nyde morphi 39 in D the production of diacetylmorphine and coined the name zoic acid,an effective preservative useful as an intestina .4.A I th Unite in typhoid fev c9 ng b (1860 During next 70 years.morphine will bem comp Acetylsalicylic acid synthesis with carbolic acid and car. withdrawn fror medical its"rehabilitation"that bon dioxide was improved by Hermann Kolbe in1874.but through ve n fact nob dy logical interes of dyin ithin hospitals order to alle Candace Pert together with Solomon Snyder (ohn human body and the use of antipyretics became ope of the Hopkins.Baltimor USA).first identife hottest fields in therapeutic research.The name of arthu 197 Figure 血1975 John UK the research and deve Hughe reported "in the head"Enkenhalins endomhins he drus with Kurt Witthaue and Julius Wol muth are to and dynorphins bind to specific receptor sites in the brain. be memorized for this historical discovery (1897)
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. Candace Pert, together with Solomon Snyder (Johns Hopkins, Baltimore, USA), fi rst identifi ed opioid receptors in the brain in 1972 28 ( Figure 1.5 ). In 1975 Hans Kosterlitz and John Hughes (Aberdeen, UK) reported the existence of an endogenous morphine-like substance 29 and named it enkephalin (for “ in the head ” ). Enkephalins, endorphins, and dynorphins bind to specifi c receptor sites in the brain. Scientifi c studies of opioid neurotransmitters during the 1970s have uncovered a complex and subtle system that exhibited impressive diversity in terms of endogenous ligands for only three major receptors. The opioid peptide precursors were subject to complex post-translational modifi cations resulting in the synthesis of multiple active peptides all of them sharing the common N-terminal sequence of Tyr-Gly-GlyPhe-(Met or Leu), which has been termed the opioid motif . Based on the results of theses studies, the endogenous opioids have been implicated in circuits involved in the control of sensation, emotion, and affect and a role has been ascribed to them in addiction, not only to opiates such as morphine or heroin, but also to alcohol. 30 2. Aspirin and NSAIDs 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 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 in 1853 33 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. 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 Arthur Eichengrün, 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). FIGURE 1.4 Aspirin and Heroin “ co-advertising ” . FIGURE 1.5 Soloman Snyder (left) and Candace Pert (right). II. Two Hundred Years of Drug Discoveries 7 Ch01-P374194.indd 7 h01-P374194.indd 7 5/29/2008 5:41:58 PM /29/2008 5:41:58 PM
CHAPTER I A History of Drug Discovery FIGURE1.6 Heinrich Dreser. It is likely that acetylsalicylic acid was synthesized under FIGURE 1.7 John Vane (Figure 1.7)developedas eneficial than the aet his fotune and prostaglandins and discovered prostacyclin.a potent platelet upon this drug which received the name of "Aspirin,"the ggregation inhibitor.John Vane explained anti-inflammatory nost familia drug name.For the first .time,an indu ct(amng which asprin remains ical the It was no until the late 1970s lin and th that aspirin's ability to inhibit prostaglandins production of aspirin administration at low dose for the prevention of by the cyclo-oxygenase enzymes was identified as the stroke or coronary attack resulted from its effect on landins enzymes regulating the prod membrane-bou the va phospholipids and released by the action of phospholi- target for new drugs.He won Albert Lasker Prize in 1977 ases.Enzymatic conversion of released arachidonic acid aobiologicalyactedenvaivespoceththioee and Nobel Prie in medicine and( Bergstrom and Bengt I.Samuelson)in 1982 3.Controversies over"coxibs" the oduction of the leukotrienes from arachidonic Another cyclo-oxygenase isoform,so-called type 2(COX-2) by the of 5-lipoxygenas overed in the ea arly 1990s by Da I Simmon mpo d th .Through pharmacological intervention in the ara ance of his discovery The same day the enzyme wa idonic acid ca ade various agents developed. The drugs. discovery.Subsequently,a new class of c COX- ch wa fter re arachidonic acid Future r ogress in this field is likely to sible for p roducing the COX-2 and revealed the enzy me' produce drugs which antagonize arachidonic acid deriva role in causing inflammation within individual cells.The tives or inhibit the enzymes involved in their sy ead by Donal Young (University of Roche ing an ingenic provid the ng of rgan called the "hlood bathed organ cascade"Iohn Vane the activity of the enzyme would be beneficial in treating
8 CHAPTER 1 A History of Drug Discovery 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 fi rst 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 of asthma. 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. 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 (with Sune Bergström and Bengt I. Samuelson) in 1982. 38 3 . 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, 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 FIGURE 1.7 John Vane . FIGURE 1.6 Heinrich Dreser . Ch01-P374194.indd 8 h01-P374194.indd 8 5/29/2008 5:41:59 PM /29/2008 5:41:59 PM
Il.Two Hundred Years of Drug Discoveries inflammation.Besides the thisCOx-2 ind an nh and cytokines stimulation.allowed to design specific inhib. in th This di ry set i tha of the enzyme and in turn reduce infammation and pain ther may be other forms of COX that could account for some c Selectiv inhibitors of COX-2 cause less endoscopically visualized FIGURE 1.8 Marc Feldmann and Ravinder Maini than tially platelet inhibitory Shih Chen (.USA) modified the as prostacyclin (PG)without coincidental inhibition thromboxane electrostatic potential of celecoxib.one of which showed agonis (IXA a substantial increase in apoptotic activity.s Whatchal. thi lenge for the future affords plausible mechanism by which COX- might enhance the risk of thrombosis in otherwise predis 4.New strategies for rheumatoid arthritis xi rheumatoid arthritis(RA),achronic infam L the withdraw controversies remain.Although the n symntomatic treatment with not interfering with selective NSAIDs can cause life-threatening g stric toxi the underlying immuno-inflammatory and disease-modifying rugs (DMA DS). modifying the dis two no COX 2 inhihitors are .or not is not theo e ing the pathogenesis of RA and definn a novel theraneutic cal.Whereas aspirin and traditional NSAIDs inhibit both arget was to investigate the role of cytokines by blocking thromboxane A2 and prostaglandin 12. the their action with antibodie on cultured synov ial-derive of COX 1 dD. might be expected to elevate blood pressure. accelerate atherogenesis,and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an mation and found that a number of pro-inflammatory plaqu present in the risk of certain cancers When celecoxih ved fo um r ne antibodies signif- icantly inhibited the generation of other pro-inflammator other COX-2 inhibitor would also prove to be safe and cytokines.Their first clinical trial was performed in 199 at Charing C d reveale apid a ffe explain this dis he The hlockade of as TNE had fa allowed to produce 50 compounds tested for their ability to reaching effects on multiple cytokines and thereby exerted induce apoptosis in human prostate cancer cells,confirmed significant anti-inflammatory and protective effects that the rec one ofjo An induction r a het sal henefit Then a erocyclic system with negative electrostatic potential and a double-blind trial supported the pro ition that TNE- benzenesulfonamide or benzenecarbonamide moiety.Ching was implicated in the pathogenesis of RA and was thus a
II. Two Hundred Years of Drug Discoveries 9 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). 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 2 ), without coincidental inhibition of the platelet agonist vasoconstrictor thromboxane (TxA 2 ). As PGI 2 counters the cardiovascular effects of TxA 2 and augments the response to thrombotic stimuli in 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. 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 I 2 , the coxibs leave 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. 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 et 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. 45 What a challenge for the future! 4 . 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 antirheumatic 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. 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 FIGURE 1.8 Marc Feldmann and Ravinder Maini . Ch01-P374194.indd 9 h01-P374194.indd 9 5/29/2008 5:42:00 PM /29/2008 5:42:00 PM