《药物化学》课程参考文献：《The Practice of Medicinal Chemistry》书籍PDF电子版（实用药物化学，第三版，Camille-Georges Wermuth，2008）.pdf_P21-P25

10 CHAPTER 1 A History of Drug Discovery 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. B . Giving back the heart its youth 1 . 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. 48 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 specifi c 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 cardiac FIGURE 1.9 Docteur Gachet (with a digital fl ower). Painting by Vincent Van Gogh. Ch01-P374194.indd 10 h01-P374194.indd 10 5/29/2008 5:42:02 PM /29/2008 5:42:02 PM

II. Two Hundred Years of Drug Discoveries 11 Na /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. 54 2 . 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. 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. 58 FIGURE 1.10 Salvadore Moncada . FIGURE 1.11 Robert Furchgott and Louis Ignarro . Ch01-P374194.indd 11 h01-P374194.indd 11 5/29/2008 5:42:03 PM /29/2008 5:42:03 PM

■12 CHAPTER I A History of Drug Discovery 3.Antihypertensive drugs Scipione Riva-Rocci (University of Pavia)introduced his ABLE 1.I Main Steps in Antihypertension Drugs ygmom 890 Veratrum alkaloids (protoveratrin) device led to many dev opments in the therapy of hype 049 Pyrogens tension disease. A fundamental role in spreading the use of the instrument was played by Harvey Cushing. 036 ThiocyanatesT Bu ire monitoring 1950 Ganglion blocking agents lear association of hy sion with heart failur 1954 Catecholamine and kidney impairment.Few years later.in 1925. the Vasodilators (hydralazine) Society of Actu alysis conce published n epidemio 960 Peripheral sympathetic inhibitors n the 1930s and 1940s.no pha antihypertensive treatment being available,physicians 1957 Diuretics (chlorothiazidel very-lov um diets erapy ose d life- 1963 Calcium channel blockers (verapamil) ent for hy in /964 B-Adrenergic inhibitor prop 1946.Blocking the sympathetic nervous system by the 969 1969 -Adrenergic inbibitors iprazosin was intr years 1976 -Blockers iabetalol,carvediloll ment for sion by 1951 65 A 1978 ACE inhibitors (captopril 100i Angiotensin(AT)receptor antagonists o the kid. ethonium and hydralazine often caused severe side effect The final drug developed in those early days,reserpi n a majorit of anti was the p an ty decades of nd h on the h unexpected diuretic action and the identification of carbonic he most demonstr ive clinical trial in the history of drug nhydrase,the enzyme responsible for transport of carbor by t ung ure Hyd nstrated that sulfanilamide wa up receivin a placebo.Previously planned to last for onic anbydrase.Various compounds with no antibacteria 5 years,the study stopped after 1 months:patients who had ffect were synthesized and,among them,acetazolamide, increased urination a Ithe pla ying at a great ith heart failu It i stin ove d to tively prove (Table 11) coma and cranial hypertension.Diuretic therapy had a dra matic effect of on hypertension.It was possible to obtain a ure and to ver fluid accumula 4.Diuretics in h nd oth A major progress was the use of diuretics,effective inability of the kidneys to regulate the salt and water bal through an increase of urine flow and sodium excretion. nce.The importance of diuretics discovery was recognize nephro 975,when the bert Las ard was gven to vailable in 1958.it

12 CHAPTER 1 A History of Drug Discovery 3 . Antihypertensive drugs Scipione Riva-Rocci (University of Pavia) introduced his mercury sphygmomanometer, easy to use and giving reliable results for measuring blood pressure, in 1896. This device led to many developments in the therapy of hypertension disease. 59 A fundamental role in spreading the use of the instrument was played by Harvey Cushing. But the importance of arterial blood pressure monitoring was not understood before 1913, when researchers reported a clear association of hypertension with heart failure, stroke, and kidney impairment. 60 Few years later, in 1925, the American Society of Actuaries published an epidemiological analysis concerning 560,000 men and demonstrating the link between cardiovascular risks and an elevated blood pressure. 61 In the 1930s and 1940s, no pharmacological antihypertensive treatment being available, physicians could choose between sympathectomy, 62 very-low-sodium diets, 63 and pyrogen therapy. 64 Those treatments had life-threatening complications or unpleasant side effects. The fi rst successful drug treatment for hypertension was introduced in 1946. Blocking the sympathetic nervous system by the means of tetraethylammonium, a drug known for 30 years to block nerve impulses was introduced few years before hexamethonium, another ammonium derivative, available as a treatment for hypertension by 1951. 65 Another effective blood pressure-lowering drug, hydralazine, 66 resulted from the search for antimalarial compounds. It was diverted to the treatment of hypertension when it was found to have no antimalarial activity but to lower blood pressure and increase kidney blood fl ow. Unfortunately, both hexamethonium and hydralazine often caused severe side effects. The fi nal drug developed in those early days, reserpine, 67 was the product of more than two decades of research into compounds derived from Rauwolfi a serpentina , a plant used for centuries by physicians and herbalists on the Indian subcontinent. 68 Antihypertensive therapy gave birth to one of the most demonstrative clinical trial in the history of drug discovery. Men with elevated blood pressure were randomly divided into two groups. Hydralazine, hydrochlorothiazide, and reserpine, were given to the fi rst group, the other group receiving a placebo. Previously planned to last for 5 years, the study stopped after 18 months: patients who had received the placebo were dying at a greater rate than those who had received the antihypertensive drugs. 69 The clinical interest of treating hypertension was defi nitively proven ( Table 1.1 ). 4 . Diuretics A major progress was the use of diuretics, effective through an increase of urine fl ow and sodium excretion. They act directly on nephrons acting on various targets, including tubules and glomerules. The fi rst thiazidic drug, chlorothiazide, became available in 1958, it was a real breakthrough, 75 and remains, 50 years later the basic diuretic used in a majority of antihypertensive regimens. Discovery of diuretic drugs followed two unrelated endeavors in the 1930s: the development of sulfanilamide 76 which had an unexpected diuretic action and the identifi cation of carbonic anhydrase, the enzyme responsible for transport of carbon dioxide by the blood and its excretion in the lungs, 77 enzyme on which, sulfanilamide is active. By 1938, physiologists demonstrated that sulfanilamide was an inhibitor of carbonic anhydrase. Various compounds with no antibacterial effect were synthesized and, among them, acetazolamide, a potent carbonic anhydrase inhibitor, increased urination and resulted in weight loss and clinical improvement of patients with heart failure and edema. It is still used to treat glaucoma and cranial hypertension. Diuretic therapy had a dramatic effect of on hypertension. It was possible to obtain a normalized blood pressure and to lower fl uid accumulation, with few side effects. Diuretics rapidly get extension of their indication in heart failure and other conditions caused by the inability of the kidneys to regulate the salt and water balance. The importance of diuretics discovery was recognized in 1975, when the Albert Lasker Award was given to Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello (Merck Sharp and Dohme Research Laboratories), TABLE 1.1 Main Steps in Antihypertension Drugs Discovery 1890 Veratrum alkaloids (protoveratrin) 70 1949 Pyrogens 1936 Thiocyanates 71 1950 Ganglion blocking agents 72 1954 Catecholamine depletors ( Rauwolfi a derivatives) 1953 Vasodilators (hydralazine) 1960 Peripheral sympathetic inhibitors (guanethidine) 1952 Monoamine oxidase inhibitors (iproniazide) 1957 Diuretics (chlorothiazide) 1963 Calcium channel blockers (verapamil) 1964 -Adrenergic inhibitors (propranolol) 73 1969 Central 2 -agonists (clonidine) 1969 -Adrenergic inhibitors (prazosin) 1976 - -Blockers (labetalol, carvedilol) 1978 ACE inhibitors (captopril) 74 1991 Angiotensin II (ATII) receptor antagonists Ch01-P374194.indd 12 h01-P374194.indd 12 5/29/2008 5:42:04 PM /29/2008 5:42:04 PM

Il.Two Hundred Years of Drug Discoveries 131 ure and of dm BOX 1.2 Ion Channels d with cardiac fail Thiazidic compounds and furosemide,another"sulfonylu Nehe rded for Nobe dicine in rea-derived"diuretic,are now universally accepted as a pri- ies concerning "the func mary treatment for hypertension uring the ionic current on a tiny membran 5.B-Blockers hannels are ifle of m cces.but ub George W.Oliver and Edward A.Schafer (University ous.Cel ǒ92 ents in and out of the cell transporting ions.The interio tal animale h don ne whic by Jokichi Takamine (1901),Friedrich Stolz performed the the cell membra t to as much as a tenth of a voll This membran 0 with ea thetic nerve increased the heart rate and the force of the ts of one protei ule or contractions in mammalians. The conditions a th cell with nchah ponds to the width of only o Stockholm)1970 Nobel Prize winning demonstrated tha ot th norepinephrine was produced by sympathetic nerves"and ating when a single ion chann rom when they are ges its sha ha of t of in tissuesand -receptors.explaining why the ber of chemical,norepinephrine,could have various effects tissular functions. This years on1963. es.UK)(Figure 1.34) ew comnounds (ver pamil and prenvlamine).mimickins ered propranolol.It was developed from the early B-adren the cardiac effects of simple Ca+withdrawal,in that they ergic antagonists dichloroisopi diminished Ca -dependent high energy phosphate uti key was s the i heart wihe or an oxymethylene bridge into the arylethanolamine struc ture of pronethalol thus greatly increasing the potency of PoVeiplpdeostaiesanaeiomclkatydistimeuithabltc the compound.By binding to the B-receptors. B-blocker from beta-receptor blockade.as it could promptly be neu are limiting the rate,dec sing the for e o with eleva d Ca scle with a significant lower Black received Nobel Prize in 1988.Since 40 y ars,many B-blockers have been synthesized.Some have slightly dif sntdced inovel dreigion Inan xtensive search for other Ca antagonists rent em s been show ble nu dihyd ang ina pamil.which is structurally similar to ine:bepridil,a non-specific calcium blocker.In 1975 6.Calcium antagonists Fumio Ariyuki.(Osaka.Japan)contributed diltiazem.a s group.Al the my dium ent rosis arising Albrecht Fleckenstein (Freiburg.Germany)observed two overload:they also

II. Two Hundred Years of Drug Discoveries 13 structural chemists and kidney physiologists responsible for chlorothiazide development for the control of high blood pressure and of edema associated with cardiac failure. Thiazidic compounds and furosemide, another “ sulfonylurea-derived ” diuretic, are now universally accepted as a primary treatment for hypertension. 5 . β -Blockers George W. Oliver and Edward A. Schafer (University College, London) demonstrated, in 1895, that an injection of adrenal gland extract could raise blood pressure in experimental animals, mimicking the stimulation of the sympathetic nervous system. 78 After epinephrine discovery by Jokichi Takamine (1901), 79 Friedrich Stolz performed in 1904 the synthesis of norepinephrine (noradrenalin) and epinephrine (adrenalin). The same year, it was suggested that sympathetic nerves produce epinephrine. 80 Physiologists demonstrated that a stimulation of sympathetic nerve increased the heart rate and the force of the heart’s contractions in mammalians. The conditions of the release of the active substance remained unknown till the 1940s, fi rst when Ulf Von Euler (Karolinska Institute, Stockholm), 1970 Nobel Prize-winning, demonstrated that norepinephrine was produced by sympathetic nerves 81 and released from them when they are stimulated. Second, with Raymond Alhquist’s (Augusta, USA) 1948 discovery, result of pure serendipity, of two types of receptors in tissues: - and β -receptors, explaining why the same chemical, norepinephrine, could have various effects on tissular functions. 82 This work fi rst refused for publication and then ignored several years, revolutionized pharmacological concepts. Fifteen years later, in 1963, James Black (Imperial Chemical Industries, UK) (Figure 1.34) discovered propranolol. It was developed from the early β -adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modifi cation, which was carried through to essentially all subsequent β -blockers, was the insertion of an oxymethylene bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. By binding to the β -receptors, β -blockers are limiting the rise in heart rate, decreasing the force of contraction, and reducing the oxygen requirements of heart muscle with a signifi cant lowering of blood pressure. 83 Black received Nobel Prize in 1988. Since 40 years, many β -blockers have been synthesized. Some have slightly different effects than propranolol, but none has been shown to be superior to propranolol in controlling hypertension or angina. 6 . Calcium antagonists The discovery of Ca antagonism as a new principle of action of coronary drugs reaches back to 1964, when Albrecht Fleckenstein (Freiburg, Germany) observed two new compounds (verapamil and prenylamine), mimicking the cardiac effects of simple Ca withdrawal, in that they diminished Ca -dependent high energy phosphate utilization, contractile force, and oxygen requirement of the beating heart without impairing the Na -dependent action potential parameters (Box 1.2). Verapamil demonstrates an action clearly distinguishable from beta-receptor blockade, as it could promptly be neutralized with elevated Ca , β -adrenergic catecholamines, or cardiac glycosides, in order to restore the Ca supply to the contractile system. 84 The term “ Calcium antagonist ” was introduced in 1969 as a novel drug designation. In an extensive search for other Ca antagonists, a considerable number of substances were identifi ed: dihydropyridines (nifedipine, amlodipine, nicardipine, nitrendipine and others); verapamil, which is structurally similar to papaverine; bepridil, a non-specifi c calcium blocker. In 1975, Fumio Ariyuki, (Osaka, Japan) contributed diltiazem, a benzothiazepine derivative to this group. All specifi c calcium antagonists interfere with the uptake of Ca into the myocardium and prevent myocardial necrosis arising from deleterious intracellular Ca overload; they also BOX 1.2 Ion Channels Erwin Neher and Bert Sakmann (awarded for Nobel Prize in Medicine in 1991 for their discoveries concerning “ the function of single ion channels in cells ” ) developed the “ patch clamp method ” proving the existence of ion molecular channels by measuring the ionic current on a tiny membrane patch to which a pre-determined voltage-clamp is applied. Ion channels are not specifi c of myocardic cells, but ubiquitous. Cell membranes of the nervous system contain a number of specifi c transport systems, which bring different agents in and out of the cell, transporting ions. The interior of the cell has a high concentration of K , whereas Na dominates on the outside. This leads to a difference in electric potential between the two sides of the cell membrane, which can amount to as much as a tenth of a volt. This membrane potential is used for a number of different tasks: the nerve cells to send rapid electrical signals, a large variety of cells to communicate with each other, etc. Every single ion channel (specifi c to one type of cation like Na or K , or anion Cl ) consists of one protein molecule or a molecular complex, which forms the walls of a thin channel, connecting the interior of the cell with its exterior, with such a small diameter that it corresponds to the width of only one single ion. When one of the channels is opened, a very small current will fl ow, which can be measured through the patch-clamp technique indicating when a single ion channel is opened or closed, that is, when a single molecule changes its shape. This technique has considerably changed pharmacological studies. A number of diseases are either infl uenced or caused by a modifi ed ion channel function: anxiety, cardiovascular disease, epilepsy, diabetes, and even reproduction. Ch01-P374194.indd 13 h01-P374194.indd 13 5/29/2008 5:42:05 PM /29/2008 5:42:05 PM

14 CHAPTER 1 A History of Drug Discovery block excitation-contraction coupling of vascular smooth muscle and, in this manner, lower Ca -dependent coronary vascular tone and neutralize all types of experimental coronary spasms. 85 7 . ACE inhibitors and sartans Among recent discoveries, the research poined out the crucial role of converting enzyme. Angiotensin-converting enzyme (ACE) inhibitors are unique in the history of antihypertensive drug development. Those antihypertensive drugs history began in 1898, when R. Tigerstedt and P. G. Bergman Swedish scientists discovered a substance in kidneys (the reason why they called it renin), raising blood pressure when injected into animals. 86 Harry Goldblatt (Cleveland, USA) ( Figure 1.12 ) revealed, in 1934, that the constriction of the renal arteries causes a chemical chain reaction leading to hypertension. 87 If Goldblatt demonstrated that hypertension could be related to a reduced blood fl ow in kidneys, the renin story remained buried more few years till experiments demonstrating in 1940, that renin was that enzyme which could act to produce angiotensin, the protein which narrows small blood vessels 88 and thus raises blood pressure. 89 By the early 1950s, research had shown that the cornerstone of this system was an enzyme, the ACE, active in a two-steps cascade. The fi rst step is the production of angiotensin I (decapeptide) from angiotensinogen consisting of 453 amino acid residues, a blood circulating protein, through the catalytic action of renin. This reaction occurs not only in plasma but also in the kidneys, brain, adrenal glands, ovaries, and possibly other tissues. The second step is the conversion of angiotensin I (with no effect on blood pressure) to angiotensin II (octapeptide) which elevates blood pressure ( Figure 1.13 ). After having discovered the amino acid sequence of angiotensin II, angiotensinogen and angiotensin I were synthesized 90 and, in a logical process, antagonists of angiotensin II were sought as treatment for hypertension. The only fruitful research came to the study of ACE inhibition itself. 91 In the 1960s, John R. Vane (London, UK) was actively investigating the cause of hypertension. During this time, a Brazilian post-doc, Sergio Ferreira, joined Vane’s group and brought with him an extract bradykinin potentiating factor (BPF) of the venom of the Brazilian viper Bothrops jararaca . This venom was found to contain compounds increasing the potency of bradykinin by blocking the enzyme, kininase II that destroys it. 92 It is a history where chance, serendipity and clear scientifi c reasoning weaved together the work of several scientists. It is also a classical example of drug development for which the initial basic research was made at the university, but the useful product was achieved by industry. 93 BPF tested on ACE was found to be a potent inhibitor thereof. This led to Vane’s strong interest in ACE and its inhibition as a means of treating hypertension. ACE was the same enzyme as kininase II. 94 Vane advocated the Squibb’s concept consisting to “ test the hypothesis ” by investigating the snake venom peptide by injection and to tackle the problem of making an orally available form of the drug. It was also necessary to demonstrate that the peptide would block the conversion of angiotensin I to II, the biochemical reaction mediated by ACE. Knowing the enzyme and its naturally occurring inhibitors from snake venom, chemists performed the synthesis of the FIGURE 1.12 Harry Goldblatt . FIGURE 1.13 The renin–angiotensin cycle. Angiotensinogen Angiotensin I Angiotensin II Aldosterone Sodium retention Alternative pathways e.g. chymase ACE Bradykinin Inactive fragments AT2 receptor AT1 receptors in adrenal gland AT1 receptors in blood vessels vasoconstriction Negative feedback Renin Ch01-P374194.indd 14 h01-P374194.indd 14 5/29/2008 5:42:05 PM /29/2008 5:42:05 PM