SOSA: THE NEW LEAD FROM OLD DRUGS

1. INTRODUCTION OF DRUG DISCOVERY

Medicinal chemists have efficient methods for optimizing the potency and the profile of a given active substance. These methods may consist of more or less intuitive approaches such as the synthesis of analogues and isomers and isosteres, or the modification of ring systems, etc. They may also rest on computerassisted design, such as identifying pharmacophores by molecular modelling or optimizing activity by means of quantitative structure activity relationships. Finally, structural biology studies yield more and more X-rays or high-field NMR descriptions of drugreceptor interactions. In each case, at the start of the process whether one is to identify a new chemical structure or a new mechanism of action, the medicinal chemist is responsible for developing as rapidly as possible more active molecules that are also more selective and less toxic. The real challenge is the absolute requirement to discover or identify an original research track. Indeed, for this major step, no codified receipt exists and the creativity of a laboratory cannot be planned. As a result, the discovery of a new lead substance represents the most uncertain stage in a drug development programme. Until the 1970s, the discovery of lead compounds depended essentially upon randomly occurring parameters such as accidental observations, fortuitous findings, hearsay or laborious screening of a large number of molecules. Since then, more rational approaches have become available, based on the knowledge of structures of the endogenous metabolites, the enzymes and the receptors, or on the nature of the biochemical disorder implied in the disease. Today, the decryption of the human genome represents a mine of potentially useful targets for which ligands have to be found.

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

SOSA: THE NEW LEAD FROM OLD DRUGS A retrospective analysis of the ways leading to the discovery of new drugs allows one to distinguish essentially four types of strategies giving rise to new lead compounds. The first strategy is based on the modification and improvement of already existing active molecules. The second one consists of the systematic screening of sets of arbitrarily chosen compounds on selected biological assays. The third approach resides in the retroactive exploitation of various pieces of biological information which result sometimes from new discoveries made in biology and medicine, and sometimes are just the fruits of more or less fortuitous observations. Finally, the fourth route to new active compounds is a rational design based on the knowledge of the molecular cause of the pathological dysfunction. 1

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DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

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2. STRATEGIES IN THE SEARCH FOR NEW LEAD COMPOUNDS

2.1. IMPROVEMENT OF EXISTING DRUGS

The First strategy is based on the modification and improvement of existing active molecules. The objective is to start with known active principles and, by various chemical transformations, prepare new molecules (sometimes referred to as me-too compounds) for which an increase in potency, a better specific activity profile, improved safety, and a formulation that is easier to handle by physicians and nurses or more acceptable to the patient are claimed. A typical illustration of this approach is found in the series of lovastatin analogues (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, etc.). In the pharmaceutical industry, motivations for this kind of research are often driven by competitive and economic factors. Indeed, if the sales of a given medicine are high and if a company is in a monopolistic situation protected by patents and trademarks, other companies will want to produce similar medicines, if possible with some therapeutic improvements. They will therefore use the already commercialized drug as a lead compound and search for ways to modify its structure and some of its physical and chemical properties while retaining or improving its therapeutic properties.

CH3 N HS O COOH
EtOOC N H O HOOC N

Captopril

Cilazaprit (Hoffmann-LaRoche)

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SOSA: THE NEW LEAD FROM OLD DRUGS

NH2

CH3

N HOOC N H O COOH
EtOOC N H

Lisinopril (Merck)

Enalepril (Merck)

COOH

Figure 1: Cptopril and

me too drugs

Other example are Antihypertensive drug captopril was used as lead compound by various companies to produce their own antihypertensive agents2. (Figure.1) Although often disparaged as mee to drugs, they can offer improvement s over the original drugs. For example, modern penicillin is more selective, more potent, and more stable than original penicillin2.

2.2. SYSTEMATIC SCREENING

This method consists in screening new molecules, whether they are synthetic or of natural origin, on animals or in any biological test without regard to hypotheses on its pharmacological or therapeutic potential. It rests on the systematic use of selective batteries of experimental models destined to mimic closely the pathological events. The trend is to undertake in vitro rather than in vivo tests: binding assays, enzyme inhibition measurements, activity on isolated organs or cell cultures, and so on. In practice, systematic screening can be achieved in two different manners. The first one is to apply to a small number of chemically sophisticated and original molecules, a very exhaustive pharmacological investigation: this is called extensive screening. The second method, in contrast, strives to find, among a great number of molecules (several hundreds or thousands), one that could be active in a given indication: this is random screening. 2.2.1. Extensive screening

Extensive screening is generally applied to totally new chemical entities coming from an original effort of chemical research or from a laborious extraction from a natural source. For such molecules, the high investment in synthetic or extractive chemistry justifies an DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 5

SOSA: THE NEW LEAD FROM OLD DRUGS extensive pharmacological study (central nervous, cardiovascular, pulmonary and digestive systems, antiviral, antibacterial or chemotherapeutic properties, etc.) to detect whether there exists an interesting potential linked to these new structures. In summary, a limited number of molecules are studied in a thorough manner (vertical derived screening). from It is by such were an approach that the these antihistaminic, and later on the neuroleptic properties of the amines phenothiazine, identified. Initially compounds had been submitted, with negative results, to a limited screening study only directed towards possible chemotherapeutic, ant malarial, trypanocidal and anthelmintic activities. More recent examples are seen by the discovery, thanks to systematic screening programme, of the cyclopyrrolones, e.g. zopiclone (Figure 2) , as ligands for the central benzodiazepine receptor,3,4 or of taxol as an original and potent anticancer drug (For a review see suffiness5)

Figure 2 : Drugs discovered by random screening.

2.2.2. Random screening In this case the therapeutic objective is fixed in advance and, in contrast to the preceding case, a great number (several thousands) of molecules is tested, but on a limited number of experimental models only. With this method one practices so-called random screening. This method has been used for the discovery of new antibiotics. By submitting samples of earth collected in countries from all over the world to a selective antibacterial and antifungal DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 6

SOSA: THE NEW LEAD FROM OLD DRUGS screening, the rich arsenal of anti-infectious drugs which are presently at the disposal of clinicians, was developed. During the Second World War, an avaian model in chickens infected with Plasmodium gallinaceum was used for the massive screening of thousands of potential antimalarials. The objective was to solve, by finding a synthetic antimalarial, the problem of the shortage of quinine. Unfortunately, no satisfactory drug was found. Massive screening was implemented in Europe and the United States to discover new anticancer6 and antiepileptic drugs. Here again the problem is to select some predictive, but cheap cellular or animal model. A common criticism of these methods is that they constitute, by the absence of a rational lead, a sort of fishing. Besides, the results are very variable: nil for the discovery of new antimalarials, rather weak for the anticancer drugs but excellent, in their time, for the discovery of antibiotics. Among the recent successes of this approach the discovery of lovastatin, also called mevinolin, should be mentioned (Figure 3), 7, 8 which was the basis of a new generation of hypocholesterolemic agents, acting by inhibition of hydroxymethyl-glutaryl-CoA reductase (HMG-CoA reductase).

Figure 3: The natural compounds compactin (mevastatin) and lovastatin block the cholesterol biosynthesis in inhibiting the enzyme hydroxymethylGlutaryl-CoA reductase (HMG-CoA reductase). The later developed Compounds, simvastatin and pravastatin, are semi synthetic analogues. The open -ring derivative pravastatin is less lipophilic and therefore Presents less central side effects. For all these compounds the ring-opened Form is the actual active form in vivo.

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2.2.3. High-throughput screening The second strategy consists of systematic screening of sets of compounds arbitrarily chosen for their diversity, by selected biological assays. This approach was useful in the past for the discovery of new antibiotics such as streptomycin and for the identification of compactin as an HMG-CoA reductase inhibitor. Presently, as high throughput screening (HTS), it is applied in a very general manner to synthetic as well as to natural compounds. Since the 1980s, with the arrival of robotics and with the miniaturization of in vitro testing methods, it has become possible to combine the two preceding approaches; in other words, to screen thousands of compounds on a large number of biological targets. This high-throughput trend is to screening replace is usually applied to the by displacement of radioligands and to the inhibition of enzymes. The present radioligand-based assays fluorescence-based measurements. As it is now possible for a pharmaceutical company to screen several thousand molecules simultaneously in 30 to 50 different biochemical tests, the problem becomes one of feeding the robots with interesting molecules. Experience gathered has confirmed that high-throughput screening allows for the rapid identification of numerous hits, and the literature is full of success stories obtained with that approach. Among them, one could mention the discovery of insulin mimetics,9 of ORL1 receptor agonists,10 of protein tyrosine phosphatase-1B inhibitors,11 of selective neuropeptide Y5 receptor antagonists,12 of selective COX-2 inhibitors,13 of corticotrophin releasing factor (CRF) receptor modulators, 14 and of CXCR2 receptor antagonists.15 Yet the HTS strategy for drug discovery has several limitations. It suffers from inadequate diversity, has low hit rates, Low-quality hits: cost and often leads to compounds with poor bioavailability or toxicity profiles.

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SOSA: THE NEW LEAD FROM OLD DRUGS In conclusion, high-throughput screening of massive libraries is expensive, time-consuming, diversity is inadequate, discovery is often limited by monotony, yield is low, and there is a risk of lowquality hits. Not surprisingly, the present trend is to use smaller libraries, and, especially, libraries with increased drug-likeness. 2.2.5. Case study 2.2.5.1. Screening of synthesis intermediates As synthesis intermediates are chemically connected to final products, and as they often present some common groupings with them, it is not inconceivable that they share some pharmacological properties. For this reason, it is always prudent also to submit these compounds to a pharmacological evaluation. Among drugs discovered in this way are the tuberculostatic semicarbazones: they were initially used in the synthesis of antibacterial sulfathiazoles. Subsequent testing of isonicotinic acid hydrazide, destined for the synthesis of a particular thiosemicarbazone, revealed the powerful tuberculostatic activity of the precursor which has since become a major antitubercular drug (isoniazide). Inhibitors of the enzyme dihydrofolate-reductase such as methotrexate (Figure 4) are used in the treatment of leukaemia. During the search for methotrexate analogues a very simple intermediate, mercaptopurine, was also submitted to testing. It proved to be active but relatively toxic. Subsequent optimization led to azathioprine, a prodrug releasing mercaptopurine in vivo. Azathioprine was found to be more potent as an immunosuppressive agent than previously used corticoids and was systematically used in all organ transplantations until the advent of cyclosporine. Another intermediate in this series, allopurinol, inhibits xanthine-oxidase and is therefore used in the treatment of gout.19

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Figure 4 :

2.3. EXPLOITATION OF BIOLOGICAL INFORMATION

A major contribution to the discovery of new active principles comes from the exploitation of biological information. By this is meant information that relates to a given biological effect (fortuitous or voluntary) provoked by some substances in man, in animals or even in plants or bacteria. When such information becomes accessible to the medicinal chemist, it can serve to initiate a specific line of therapeutic research. Originally, the observed biological effect can simply be noticed without any rational knowledge on how it works. 2.3.1. Exploitation of observations made in man The activity of exogenous chemical substances on the human organism can be observed under various circumstances: ethnopharmacology, popular medicines, clinical observation of secondary effects or adverse events, fortuitous observation of activities of industrial chemical products, and so on. Since in all

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SOSA: THE NEW LEAD FROM OLD DRUGS cases the information harvested is observed directly in man, this approach represents a notable advantage. 2.3.1.1. Study of indigenous medicines (ethnopharmacology ) Natural substances were for a long time the unique source of medicines. At present, they constitute 30% of the active principles used and probably more (approximately 50%) if one considers the number of prescriptions that utilize them, particularly since use of antibiotics plays a major role.20 Behind most of these substances one finds indigenous medicines. As a consequence, ethnopharmacology represents a useful source of lead compounds. Historically, we are indebted to this approach for the identification of the cardiotonic digitalis glucosides of the digital, the opiates and the cinchona alkaloids. Despite its extremely useful contributions to the modern

pharmacopoeia such as artemisin, and huperzine, folk medicine is a rather unreliable guide in the search for new medicines. When ethnopharmacology and the natural substance chemistry end in the discovery of a new active substance, this latter is first reproduced by total synthesis. It is then the object of systematic modifications and simplifications that aim to recognize by trial and error the minimal requirements that are responsible for the biological activity. 2.3.1.2. Clinical observation of side-effects of medicines The clinical observation of entirely unexpected in side effects

constitutes a quasi in exhaustible source of tracks for lead compounds. Indeed, besides the

the search

desired therapeutic action, most drugs possess side-effects. These are accepted either from the beginning as a necessary evil, or recognized only after some years of use. When side effects present a medical interest in themselves, a planned objective can be the dissociation of the primary from the side-effect activities: enhance DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 11

SOSA: THE NEW LEAD FROM OLD DRUGS the activity originally considered as secondary and diminish or cancel the activity that was initially dominant. Promethazine, for example, an antihistaminic derivative of phenothiazine,
21

has

important sedative effects. Like Laborit et al., towards better-profiled analogues.

a clinician might

promote the utilization of this side-effect and direct research This impulse was the origin of chlorpromazine, the prototype of a new therapeutic series, the neuroleptics, whose existence was previously unsuspected and which has revolutionized the practice of psychiatry.10,
22

Innumerable other examples can be found in the

literature, such as the hypoglycaemic effect of some antibacterial sulfonamide, the uricosuric effect of the Coronary-dilating drug benziodarone, agents. the antidepressant effect of isoniazid, an antitubercular drug, and the hypotensive effect of -blocking

This last example is beautifully illustrated by the discovery of the potassium channel activator cromakalin.23 antihypertensive agent shown to Cromakalin is the first act exclusively through

Figure 5: The clinical observation of the hypotensive Activity of the open (and therefore flexible) -blocking of -blocking activity, but retaining the antihypertensive activity.23

potassium channel activation.24 This novel mechanism of action involves an increase in the outward movement of potassium ions through this channels in the membranes of vascular smooth muscle can be summarized as follows: -Adrenergic cells, leading to relaxation of the smooth muscle. The discovery of compound

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SOSA: THE NEW LEAD FROM OLD DRUGS Receptor blocking drugs were not thought to have antihypertensive effects when they were first investigated. However, pronethalol, a drug that was never marketed, was found to reduce arterial blood pressure in hypertensive patients with angina pectoris. This antihypertensive effect was subsequently demonstrated for propranolol and all other-adrenergic antagonists.25 Later there were some doubts that blockade of the adrenergic receptors was responsible for the hypotensive activity and attempts were made, in the classical -blocking molecules, to dissociate the -blockade from the antihypertensive activity. Among the various conceivable molecular variations which are possible for the flexible -blockers, it was found that conformational restriction obtained in cyclizing the carbon atom bearing the terminal amino group on to the aromatic ring yielded derivatives devoid of b-blocking activity, but retaining the antihypertensive activity (Figure 5). One of the first compounds prepared (compound 1, Figure 5) was indeed found to lower blood pressure in hypertensive rats by a direct peripheral vasodilator mechanism; no -blocking activity was observed. Optimization of the activity led to the 6-cyano-4 pyrrolidinyl- benzopyran (compound 2), which was more than 100-fold more potent than the nitro derivative. The replacement of the pyrrolidine by a pyrrolidinone (which is the active metabolite) produced a three-fold increase in activity and the optical resolution led to the (-)-3R, 4S enantiomer of cromakalim (BRL 38227), which concentrates almost exclusively the hypotensive activity.
23, 26, 27

2.3.1.3. New uses for old drugs In some cases a new clinical activity observed for an old drug is sufficiently potent and interesting to justify the immediate use of the drug in the new indication.

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SOSA: THE NEW LEAD FROM OLD DRUGS Amiodarone, for example (Figure 6), was introduced as a coronary dilator for angina. Concern about corneal deposits, discoloration of skin exposed to sunlight and thyroid disorders led to the withdrawal of the drug in 1967. However, in 1974 it was discovered that amiodarone was highly effective in the treatment of a rare type of arrhythmia purpose.28 known as the Wolff-Parkinson-White syndrome. Accordingly, amiodarone was reintroduced specifically for that

Figure 6:

Benziodarone, initially used in Europe as a coronary dilator, proved later to be a useful uricosuric agent. At the present time it is withdrawn from the market due to several cases of jaundice associated with its use.28 the corresponding brominated analogue, benzbromarone, properties. Thalidomide, was initially launched as a sedative/hypnotic drug (Figure 7), but withdrawn because of its extreme teratogenicity. Under restricted conditions (no administration during pregnancy or to any woman of childbearing age), it found a new use as an immunomodulator. Particularly, it seems efficacious for the treatment of erythema nodosum leprosum, a possible complication of the chemotherapy of leprosy.29 was specifically marketed for its uricosuric

Figure 7: Structure of thalidomide. The marketed compound is the racemate.

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SOSA: THE NEW LEAD FROM OLD DRUGS

A more recent example is provided by the discovery of the use of sildenafil (Viagra, Fidure 8), a phosphodiesterase type 5 (PDE5) inhibitor, as an efficacious, orally active agent for the treatment of male erectile dysfunction.30, 31 Initially this compound was brought to the clinic as a hypotensive and cardiotonic substance and its usefulness in male erectile dysfunction resulted from clinical observations.

Figure 8: Structure of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil. 30,12

In many therapeutic families each generation of compounds induces the birth of the following one. This happened in the past for the sulfamides, penicillins, steroids, prostaglandins and tricyclic psychotropic families, and real genealogical trees representing the progeny of the discoveries can be drawn. More recent examples are found in the domain of ACE inhibitors and in the family of histaminergic H2 antagonists. Research programmes based on the exploitation of side effects are of great interest in the discovery of new tracks in so far as they depend on information about activities observed directly in man and not in animals. On the other hand, they allow detection of new therapeutic activities even when no pharmacological models in animals exist.

2.3.2. Exploitation of observations made in animals Here, we find all the research done by physiologists which has been the basis of the discovery of vitamins, hormones and neurotransmitters and the fall-out of various pharmacological DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

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SOSA: THE NEW LEAD FROM OLD DRUGS studies, when they were performed in vivo. Other observations made on animals, often in a more or less fortuitous manner, have led to useful discoveries. An example is provided by the dicoumarolderived anticoagulants. The discovery of the anticancer properties of the alkaloids of Vinca rosea constitutes a particularly beautiful example of pharmacological feedback. Preparations from this plant had the reputation in some popular medicines of possessing anti diabetic virtues. During a controlled pharmacological test, these extracts were proved to be devoid of hypoglycaemic activity. On the other hand, it was frequently observed that the treated rats died from acute septicaemia. A study of this phenomenon showed that it was due to massive leukopenia. Taking the leukocyte count as the activity end-point criterion, it became possible to isolate the main alkaloid, vinblastine.32 at the same time, in another laboratory, routine anticancer screening had revealed the activity of the crude extract on murine leukaemia.33 subsequently, and the antileukaemic acvity became a screening tool. Out of 30 alkaloids isolated from various periwinkles, four (vinblastine, vinleurosine, vincristine and vinrosidine) were found active in human leukaemias.34

3. DRUG DISCOVERY FROM SOME SIDE SIDE EFFECT OR NEW LEADS FROM OLD DRUGS 3.1. INRTODUCTION

Many important therapeutic discoveries have resulted from serendipitous observation. Side effect of drug candidate in the clinical has paved the way to new application of a drug or to a development of chemically modified analogs. Unexpected pharmacological effect against physiologically related or other, more diverse, targets have resulted in drug candidates with different modes of action. In the past decades, more systemic approaches have been followed: chemo genomics, systemic DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 16

SOSA: THE NEW LEAD FROM OLD DRUGS investigation of biological effects of certain target families, and the selective optimization of drug side effects (SOSA)52. Such side effect may result from: A physiological reaction of the body to the action of the drug (e.g., the reflex tachycardia resulting from the antihypertensive activity of dihydropyridine calcium channel blocker). Overdose of drug with narrow therapeutic range and/or unfavorable pharmacokinetics (e.g., phenprocoumon or warfarin, which exert their action in delayed and indirect manner by inhibition of vitamin k biosynthesis). Action of different target by same mechanism (e.g., gastrointestinal bleeding after cyclooxygenase inhibition by acetylsalicylic acid, bradykinin-mediated cough as a side effect of angiotensin converting enzyme inhibitors). Action on organs other than the target organ (peripheral tachycardic and hypertensive effects of dopamine after systemic application of the antiParkinson drug L-dopa, sedative e side effects of lipophillic histamine H1 antagonist). Lack of selectivity, i.e., inhibition, agonism, antagonism at several different targets, a most common reason for drug side effect (e.g., respiratory depression by morphine, cardio tonicity of certain drugs mediated by hERG channel inhibitions). Inhibition of cytochrome P450 isoenzymes (e.g., nonlinear pharmacokinetic propafenone, producing an exponential increase of plasma level due to inhibition of its metabolism by CYP2D6, after application of higher dose). Drug-drug interaction resulting from P450 inhibition or induction, a very common reason for adverse drug effects (e.g., terfenadine which exerts fatal cardio toxicity by hERG channel inhibition in the presence of a CYP3A4 inhibitor, where its active metabolite fexofenadine is not a hERG channel inhibitor). Genetic deposition, either by interaction of drug with mutant target or by the lack of certain (or mutant) metabolic enzyme (e.g., inability of about 1-3% Caucasian population to metabolite S-warfarin, due to aCYP2C9 deficiency).

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SOSA: THE NEW LEAD FROM OLD DRUGS There must always be significant advantage of the achievable therapeutic benefits, as compared to the risk of drug-related side effects. Several side effects can only be tolerated in treatment of chronic degenerative or life-threatening disease like arthritis, cancer, or AIDS. However, adverse drug side effect are frequently observed after medication; their high incidence, even as a common cause of death, is only gradually being recognized. However, a closer inspection history of drug discovery show that many new drug application resulted from clinical observation of side effects or from the optimization of such unexpected side effects into new therapeutic areas Only the prominent drugs that resulted from serendipitous observation of clinical side effects are discussed in following sections. However, even few examples show the importance of this source of new leads in drug research. In addition to clinical observation of drug side effects, the optimization of side activities that are discovered by in vitro investigation play important role in drug research. Recently wermuth proposed using this approach as a general strategy for the selective optimization of side activities (the SOSA approach)52 .

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3.2. A HISTORICAL PERSPECTIVE: THE GREAT TIME OF SERENDIPIOUS OBSERVATION

The early history of drug discovery is characterized by many serendipitous drug discoveries. After the preparation of nitrous oxide by Humphry Davy in the early 19th century, fun patient with this gas, and also with ether became popular, people liked the euphoric after inhaling the chemicals. The anesthetic property of nitrous oxide and the were discovered in the 1840s just by chance, because participants of such events did not expiernced any pain after being hurt52. A more or less systemic search for new drug started in the last two decades of the 19th century. Although acetylsalicylic acid 1 (ASS, aspirine, bayer, figure 10) was originally designed as a better derivative of salicylic acid, it is much more than just prodrug. ASS is much more active than its parent drug is indeed better tolerated, but it causes gastrointestinal bleeding as a prominent side effect. In the 1970s it became clear that both its activity and its side effects are mediated by the same target. ASS inhibits cyclooxygenase, which converts arachidonic acid into prostacyclin, which is further converted into prostaglandins and thromboxane. Whereas inhibition of thromboxane biosynthesis is responsible for the increased bleeding tendency. Since thromocyte have no nucleus and therefore no protein biosynthesis, platelet cyclooxygenase remains inhibited over the whole thrombocyte lifetime of about 120 days; correspondingly thrombosis protection by aggregation inhibition can be achieved by application of only 100 mg or even less of ASS per day. Low-dose ASS is now standard therapy for the preparation of stroke, heart attack and thrombosis.
COOH O CH3

Figure 10: ASS 1 is much more than prodrug of salicylic acid. Its major Contributions to biological activity come from unique mechanism of action: The activated acetyl group is transformed to serine hydroxyl group in the binding site of cyclooxigenase.

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The diuretic organomercurials are most probably the very first example of discovery of a class of therapeutically useful drug by a clinical side effect of one of their mechanisams.In1988, mercury salicylate was introduced for the treatment of syphilis , followed by mersanyl in 1906 and arsphenamine (E. 606),discovered by Paul Ehrlich in 1909. On October 7, 1919, a pale and weak 21-years-old female, Johanna M., was brought to first medical university Clinic I Vienna, in am insane status , with clear symptoms of severe neurosyphillis. Alfred Vogel, a 3 rd -year medical student, was ordered to apply mercury salicylate, in a desparate attempt to help. No knowing about properties of this compound, he asked for 10% aqueous solution for intramuscular injection. After few days when he has not received the solution, he was told that the compound was too insoluble. A colleague proposed trying recently developed analog, merbaphen (Novasurol, bayer, figure 11), and a water insoluble salt of organomercurial compound with barbitone.
Cl O COO-Na+

O Et HN Et

Hg+

2
Figure 11 merbaphen Mebaphen 2 was the first example of an organomercurial diuretic: some drug with less side effect were therapeutic standard from about 1920 to 1950.

After approval by his superviser, he applied it to suffering patient. To this great surprise, the daily urine production increased from 200-500 mL. Application to other patients produced up to 10 L urine within 24 hours a diuretic effect that had not been observed before !Merbaphen was too toxic for therapeutic application, but follow-on product held their place as diuretic till the 11950s, when another observation of clinical side effect led to the discovery of much safer sulphonamide diuretic52.

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SOSA: THE NEW LEAD FROM OLD DRUGS

Cl H N H N

N Cl

17 Clonidine
Figure 14

14 )

The aniline-imidazoline clonidine 17 (Catapresan, boehringer ingelheim;figure was designed by she mist Helmut Staehle as nasal deconjestant.When the secreatory of the colleague caught a nasty cold, she was ready to test the new drug. Telling them I will take anything if I can just get rid of this stifles! Shortly after taking the drug she became tired and fell asleep, After she was brought home, she continue sleeping for about 20 hours. A controlled self-experiment by her boss, the physician Martin Wolf ,had same outcome, with a heart rate reduction to about 40-48 beats s1 and blood pressure decrease to 90 vs. 60 mm Hg. Clearly, the compound was potent antihypertensive drug, which was confirmed by further pharmacological and clinical investigations52.
O H N N H R

18 Iproniazide 19 Isoniazide

Figutr 15

Iproniazide 18 (figure 15).an alkyl analog of the antituberculous drug isoniazide 19(figure 15),surprisingly shows mood improving activity in several depressed tuberculosis patients, which turned out to result from monoamine oxidase (MAO) inhibitory activity. Since the compound was already registered as antituberculosis drug and since its constituted the very first effective treatment of depression, more than 400 000 patient received it within only one year after the first announcement

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SOSA: THE NEW LEAD FROM OLD DRUGS of its antidepressant activity52.Later it was withdrawn from therapy ,due to hepatotoxic side effect.

Me Me HS

H COOH CH3
Figure 16

20 D-penicillamine

D-Penicillamine 20 (figure 16) has for long time been used for the treatment of Wilsons disease, a metabolic disorder in which absorbed copper is deposited mainly in the liver and in the brain. Long term application of this compound leads to suppression of rheumatoid arthritis, which now is its main therapeutic use 52.

Me O H N

Me O H N N N N

HN

O N

HN

21 Sulphonamide analog 20 Zaprinast

O O S t-But

N H

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SOSA: THE NEW LEAD FROM OLD DRUGS

Me

O H N N N N

HN

N O O S N

Me

22 Sildenafil

Figure 17

Sildenafil (Viagra, Pfizer), the first drug effective in male erectile dysfunction (MED), has very interesting history. More than 30 years ago, the company May & Baker started research on antiallergic and 22 xanthine derivatives. Their first leads 21 (figure 17) , being between 40 times and 100 times more active than

cromoglycate, the standard drug at this time , were structurally closely related to sildenafil. Zaprinast 21, was clinically tested orally active mast cell stabilizer against histamine- and exercised-induced asthmas. In addition to this activity, zaprinast has vasodilatory and antihypertensive side effects. In the mid 1980s , Nick Terret and his teamm at Pfizer were searching for new antihypertensive principle . They followed the approach of enhancing biological activity of the atrial natriuretic peptide (ANP) by prolonging the action of the second messenger of the corresponding receptor response. For this purpose, they were looking for a compound they would prevent the degradation of cyclic guanisone monophosphate (cGMP) by phosphodiesterse. As zaprinast 21 was one of very few cGMP PDE inhibitors known in 1986, they started from this lead to improve its activity and selectivity .In 1989, the result of extensive structure modification was the PDE5selective inhibitor sildenafil 23 (UK-92,480;figure 8), later clinically tested as antianginal drug .The drug turned out to be safe and well tolerated but its clinical activity was disappointing. However, early in 1992, a 10-day toleration study in healthy volunteers led to observation of a strange side effect. Among other effects , the the patient reported some penile erections after the 4th or 5th day. Although it was not an obvious choice to test the new drug in male erectile dysfunction,its further clinical profiling went into this direction. After convincing clinical results, Viagra was introduced into therapy in March 198852.

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SOSA: THE NEW LEAD FROM OLD DRUGS

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4. SELECTIVE OPTIMIZATION OF SIDE ACTIVITY: THE SOSA APPROACH

Selective optimization of side activities of drug molecules (the SOSA approach) is an intelligent and potentially more efficient strategy than HTS for the generation of new biological activities. Only a limited number of highly diverse drug molecules are screened, for which bioavailability and toxicity studies have already been performed and efficacy in humans has been confirmed. Once the screening has generated a hit it will be used as the starting point for a drug discovery program. Using traditional medicinal chemistry as well as parallel synthesis, the initial side activity is transformed into the main activity and, conversely, the initial main activity is significantly reduced or abolished. This strategy has a high probability of yielding safe, bioavailable, original and patentable analogues.53

4.1. DEFINATION, PRINCIPLES AND METHODOLOGY.

The SOSA (selective optimization of side activities) approach represents a validated alternative to HTS
(56-60)

. It consists of testing old drugs on new pharmacological

targets. The aim is to subject to pharmacological screening a limited number of drug molecules that are structurally and therapeutically very diverse and that have known safety and bioavailability in humans and thereby shorten the time and the cost needed for a hit identification. The SOSA approach proceeds in two steps. (1) Start the screening with a limited set of carefully chosen, structurally diverse drug molecules (a smart library of about 1000 compounds). Since bioavailability and toxicity studies have already been performed for those drugs and since they have proven their usefulness in human therapy, all hits will be drug like! (2) Optimize hits (by means of traditional, parallel, or combinatorial chemistry) in order to increase the affinity for the new target and decrease the affinity for the other

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SOSA: THE NEW LEAD FROM OLD DRUGS targets. The objective is to prepare analogues of the hit molecule in order to transform the observed side activity into the main effect and to strongly reduce or abolish the initial pharmacological activity. As mentioned above, a differentiating peculiarity of this type of library is that it is constituted of compounds that have already been safely given to humans. Thus, if a compound were to hit with sufficient potency on an orphan target, there is a high chance that it could rapidly be tested in patients for proof of principle. Alternatively, if one or more compounds hit but with insufficient potency, optimized analogues can be synthesized and the chances that these analogues will be good candidate drugs for further development are much higher than if the initial lead is toxic or not bioavailable. One of these new types of chemical library has recently become available 61. It contains 880 biologically active compounds with high chemical and pharmacological diversity as well as known bioavailability and safety in humans. Over 85% of the compounds are well-established drugs, and 15% are bioactive alkaloids. For scientists interested in drug likeness, such a library certainly fulfills in the most convincing way the quest for drug like leads! Other libraries containing various amounts of drug molecules are also available62, 63.

4.3. RATIONAL OF THE SOSA APPROACH.

The rationale for using chemical libraries composed of marketed drugs is that most drugs used in humans interact with more than one target/receptor. Binding to one target mediates efficacy, whereas binding to other targets is often the source of side effects. There are many published examples of drugs that interact with several receptors. The anxiolytic diazepam not only binds to the benzodiazepine receptor but also inhibits phosphodiesterases64. The GABA-A receptor antagonist gabazine is a potent inhibitor of monoamine-oxidase type A65.

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SOSA: THE NEW LEAD FROM OLD DRUGS Compounds as different as benzyl penicillin or D-tubocurarine unexpectedly shows micro molar affinity for GABA-A receptors66. N--Nitroarginine, a competitive antagonist of nitric oxide synthesis, was also shown to be a muscarinic receptor antagonist67. The dopamine receptor antagonist spiperone shows a strong affinity for serotonin 5-HT2a receptors68. Other antipsychotic such as clozapine and olanzapine have been shown to bind To at least 14 different receptors such as D1, D2, D3, 5-HT2a, 5-HT2c, 5-HT3, M1, M2, M3, M4, M5, R1, R2, and H1 receptors67. This seems to be a Rather common feature as shown in Table 1 (results from Schaus and By masters review69), which compares some affinities for a series of eight antipsychotic agents. Table 1 : Affinities of Some Antipsychotic for Various Neuronal Receptors70

The above observations justify the strategy of testing well-known drugs on newly discovered targets. When an old drug binds to a new target, the objective is to synthesize analogues with increased affinity for the new target and decreased affinity for the old target. Many examples of such activity profile reversals have been published and are usually the result of traditional, well established medicinal chemistry approaches.

4.4. APPLICATION OF SOSA APPROACH : Successful Examples of SOSA Switches

4.4.1. Sulfonamides as Lead Compounds.

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SOSA: THE NEW LEAD FROM OLD DRUGS Two examples of SOSA switches show that extremely potent and selective antagonists of G-protein-coupled receptors and myocardiac sodium/hydrogen exchange (NHE) inhibitors could be derived from traditional drugs such as sulfathiazole and amiloride. 4.4.1.1. From Sulfathiazole to Endotheline ET-A Receptor Antagonists.

A typical illustration of the SOSA approach is given by the development of selective antagonists for the endothelin ET A receptors by scientists from Bristol-Myers Squibb (BMS)71. Starting from an in-house library, the antibacterial compound sulfathiazole 1 (Figure 21) was an initial, but weak, hit (ETA IC50 = 69 M). Testing of related sulfonamides identified the more potent sulfisoxazole 2 (ETA IC50 = 0.78 M). Systematic variations finally led to the potent and selective ligand 3 (BMS-182874). This compound was orally active in vivo and produced a long-lasting hypotensive effect.

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SOSA: THE NEW LEAD FROM OLD DRUGS Figure 21. A successful SOSA approach identified the Antibacterial sulfonamide Sulfathiazole as a ligand of the Endothelin ETA receptor and its optimization to the Selective and potent compounds BMS-182874, BMS-193884, and BMS207940.71,72 Further optimization guided by pharmacokinetic considerations led the BMS scientists to replace the naphthalene ring by a biphenyl system72. Among the prepared compounds, 4 (BMS-193884, ETA Ki = 1.4 nM; ETB Ki = 18,700 nM) showed promising hemodynamic effects in a Phase II clinical trial for congestive heart failure. Morerecent studies led to the extremely potent antagonist 5 (BMS207940, ETA Ki = 10 pM) representing an 80,000-fold selectivity for ETA over ETB. The oral bioavailability of 5 is 100% in rats and it has been shown to possess activity at a dose of 3 g/kg by mouth [per os (p.o.)]72.

4.4.1.2.

Diuretic Amiloride as a Lead to Myocardiac Sodium/Hydrogen Exchange (NHE) Inhibitors.

Figure 22. Amiloride-derived cardio protective sodium/hydrogen exchange (NHE) inhibitors. Currently, five isoforms of sodium/hydrogen exchanger have been found in the plasma membrane of mammalian cells and a sixth has been found in the mitochondria73. The predominant isoform in the heart is type 1 (NHE-1). One of the first papers to suggest a cardioprotective role of inhibiting NHE was published by DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 29

SOSA: THE NEW LEAD FROM OLD DRUGS Karmazyn in 198874 where it was shown that amiloride 6 (Figure 22), a potassiumsparing diuretic with NHE inhibitory activity, produced an enhanced recovery of contractile function in isolated rat hearts subjected to global ischemia and reperfusion. Subsequently, several investigators used amiloride and its 5-amino substituted pyrazinoyl guanidine derivatives to demonstrate the cardioprotective potential of inhibiting NHE in the ischemic myocardium.73,75 However, it was found later that these amiloride derivatives interacted with other cation transporters and shared cardio depressive activities independent of their NHE blocking activity. Investigators at Hoechst75 were the first to synthesize a new class of more selective NHE-1 inhibitors, the benzoylguanidine derivatives 7 and 8 (Figure 22). The first compound showing superior efficacy and selectivity over amiloride derivatives was 7 (Hoe-694). This compound showed marked anti arrhythmic and anti ischemic activity in several animals models and had a low toxicity profile. To synthesize a compound superior to 7, investigators from Hoechst made 8 (Hoe-642, or cariporide mesilate) by substituting an isopropyl for a piperidine group. This change enhanced water solubility, activity in vitro, and NHE-1 selectivity over 7. Subsequently, other companies, for example, Merck KGaA and Boehringer, also synthesized benzoylguanidine derivatives such as 9 (EMD-96785, or eniporide mesilate) and 10 (BIIB-513)76. All these compounds have been shown to be cardioprotective in a number of ischemic animal and human models. 4.4.2. Dihydropyridines as Leads. Retrospective analyses of various drug structures led the medicinal chemists to identify some molecular motifs that are associated with high biological activity more frequently than other structures. Such molecular motifs were called privileged structures by Evans et al77. to mean substructures that confer activity on two or more different receptors. The implication was that the privileged structure provides the scaffold and that the substitutions on it provide the specificity to a particular receptor. Two monographs deal with the privileged structureconcept78,79. The Ca2+ channel blockers containing the dihydropyridine motif certainly belong to the class of privileged stuctures80. We will discuss how they served as a starting point

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SOSA: THE NEW LEAD FROM OLD DRUGS for the synthesis of 1A-adrenergic antagonists and of multi drug-resistance modulators. 4.4.2.1. Calcium Channel Blocker Niguldipine as a Source of 1A-Adrenergic The typical symptoms of prostatism are obstructive (poor urine stream, dribbling, large residual urine volume) and irritative (hesitancy, increased frequency of urination, nocturia) in nature and can significantly compromise the quality of life of patients. While surgical procedures or the use of 5 reductase inhibitors such as finasteride are used to reduce the prostatic mass, 1-adrenergic receptor antagonists such as terazozin, doxazocin, and tamsulosin relax the smooth muscles in the prostate and in the lower urinary tract and facilitate the urine flow. Antagonists81.

FFigure 23. Passage from the calcium channel antagonist niguldipine to the potent and selective 1A-Adrenergic antagonist 14 (SNAP-6383)81. However, nonselective 1-adrenergic receptor antagonists present cardiovascular side effects (tachycardia and orthostatic hypotension). Selective blockers of the 1Asubtype of adrenergic receptors are assumed to alleviate the symptoms associated with benign prostatic hyperplasia (BPH) with minimal cardiovascular side effects. A screening program identified the calcium channel blocker niguldipine 11 (Ki = 4.6 nM for rat L-type calcium channel) as a potent ligand ( Ki = 0.16 nM) of the recombinant human 1A-adrenoceptor (Figure 23). Moreover, niguldipine presents considerable 1A -selectivity (>300-fold over 1B- and 1D-receptors. Niguldipine was developed as a racemate; however, the 1-adrenergic receptor antagonist properties are mainly concentrated in the (S)-(+)-enantiomer. During mutation studies of a series of R1A-adrenergic ligands, it appeared that mutation of either Phe-308 or Phe312 in the transmembrane domain 7 of the 1A-receptor results in significant losses of affinity (4- to 1200-fold) for the antagonists prazosin, WB4101, BMY7378, ( S)- (+)DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 31

SOSA: THE NEW LEAD FROM OLD DRUGS niguldipine, and 5-methyluradipil. No affinity changes were observed for the phenyl ethylamine type of agonists82. Progressive optimization of niguldipine yielded compounds such as 12 (SNAP-5089 (-)), 13 (SNAP-5399), and 14 (SNAP-6383)81. These compounds display nanomolar affinities for the 1A-receptor subtype, which correlates well with the potency to inhibit the phenylephrine induced contraction of dog prostate. Compound 14 binds to the human recombinant 1A adrenergic receptor with a Ki of 0.36 nM and exhibited a 1000-fold selectivity improvement over other subtypes83. It proved to be efficacious in clinical trials but was finally discarded for its cytochrome P450 3A4 isozymemediated metabolism and the corresponding risk of drug-drug interaction81.

Figure 24. Monatepil maleate (15) combines calcium channel blocking activity, 1-adrenoceptor antagonism, and inhibition Of lipid hydroperoxidation.84,86 A similar finding associating calcium channel blocking activity with 1-adrenoceptor antagonism is found in the drug monatepil maleate (15, Figure 24).84-86 In addition to the above-mentioned properties, monatepil maleate was shown to potently inhibit copper-induced lipid hydroperoxidation of human LDL in vitro86. 4.4.2.2. Dihydropyridine-Type Calcium Channel Blockers as a Source of Multi drug- Resistance Modulators 87-89.

Figure25. Dexniguldipine 16, the (R)-(-)-enantiomer of DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 32

SOSA: THE NEW LEAD FROM OLD DRUGS Niguldipine, is less active as a calcium channel blocker but Potent as a reverser of multidrug resistance. One type of resistance of neoplastic cells to cytotoxic agents is multidrug resistance, which may occur spontaneously or develop as a response to exposure to several different drugs, including anthracyclines, actinomycin D, epipodophyllotoxins, taxanes, and vinca alkaloids. The transmembrane glycoprotein, 170 kDa Pglycoprotein90, actively extrudes susceptible drugs by pumping them out of the cell by an ATP requiring process. P-glycoprotein is encoded by the multidrug resistance-1 gene (MDR1), which is on the long arm of chromosome 7. Multidrug resistance is due to over expression of P-glycoprotein and perhaps other factors. Some compounds, such as the calcium channel blocker verapamil, by binding to Pglycoprotein, increase the intracellular accumulation of the drugs that are actively extruded. The less active (R)-(-)-enantiomer of niguldipine, dexniguldipine (Figure 25), is a dihydropyridine derivative, which weakly blocks calcium channels 86 and shows promise as a reverser of multidrug resistance 86. It only has 1/40 the affinity for the L-type calcium channel as its enantiomer, niguldipine 91. It is also much less active at blocking calcium channels than verapamil and has less cardiovascular effects than verapamil. P-glycoprotein has an intracellular drug acceptor with which dexniguldipine combines. Dexniguldipine binds on receptor site 2 of P-glycoprotein, whereas verapamil, cyclosporine A, etoposide, and vinblastine all bind at receptor site 192. Dexniguldipine inhibits protein kinase C93, is a calmodulin antagonist94, has antitumor activity94-95, and inhibits DNA synthesis in experimental tumors96. Dexniguldipine is about 10 times as potent as verapamil at reversing multidrug resistance in many in vitro systems.97 4.4.3. Cyclic Analogues of -Blockers. Conventional -blockers possess a number of pharmacological properties, e.g., blocking, quinidine-like, local anesthetic, and hypotensive effects. With the hope of achieving some specificity, Basil et al98. Considered the possibility of synthesizing ring-closed analogues (closure mode 1; Figure 26). One of the prepared compounds, 3,4-dihydro- 3-hydroxy-6-methyl-1,5-benzoxazocine, was a potent -blocker. This activity is unlikely to be due to hydrolysis to the open-chain derivative because the corresponding primary amine, formed by hydrolysis of the benzoxazocine ring, has DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 33

SOSA: THE NEW LEAD FROM OLD DRUGS less than 0.25 the activity of the latter. Yet it is difficult to reconcile the benzoxazocine configuration with the structural requirements associated with the occupation of -receptors.

Figure26. Cyclized analogues of -blocking phenylpropanolamines.98,99,102 Attempts to exploit the sedative and anticonvulsant effects observed for propranolol in pharmacological experiments prompted Greenwood et al 99. to examine the closure mode 2 (Figure 26). Their study led to the norepinephrine reuptake inhibitor viloxazine, which was the first representative of a new class of antidepressant. Later, Evans et al100-101. Envisaged the closure mode 3 (Figure 26) for the synthesis of cyclized analogues of the phenylpropanolamine type of -blockers. The authors hoped that by restricting the conformation, -blocking activity would be lost but antihypertensive activity might be retained. This turned out to be true in animal tests and in double-blind clinical studies and justified the development of the potassium channel activator cromakalim102. This compound itself was further developed to yield IKs channel blockers as potential antiarrhytmic agents. 4.4.3.1. From -Blockers to the Potassium Channel Blocker Cromakalim. A near-textbook illustration of the SOSA concept is given by the development of the hypotensive drug levocromakalim starting from -blockers such as atenolol102. Blockers were introduced in the early 1970s for the treatment of angina pectoris and hypertension. However, there was some doubt that -blockade was responsible for their antihypertensive activity and it was suggested that analogues with reduced flexibility of the side chain may be devoid of -blocking activity but would retain the antihypertensive activity. This was the initial lead to cyclized analogues (Figure 27). DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 34

SOSA: THE NEW LEAD FROM OLD DRUGS

Figure 27. Passage from open- -blockers to the corresponding cyclized analogues102. One of the first compounds prepared was compound 17, which for chemical reactivity reasons bore gemdimethyl group at C-2. This compound was indeed found to lower blood pressure in hypertensive rats by a direct peripheral vasodilator mechanism; no -blocking activity was observed. Optimization of the activity led to compound 18, which was more than a 100-fold more potent than the nitro derivative. The replacement of the pyrrolidine by a pyrrolidinone (which is the active metabolite) produced a 3-fold increase in activity. Finally, the optical resolution led to the ( -)-(3S,4R)- enantiomer of cromakalim 19 (levocromakalim, BRL 38227) that concentrates almost exclusively the hypotensive activity and acts exclusively as a potassium channel opener; -blocking activity is no longer observed. 4.4.3.2. IKs Channel Blockers as Potential Anti arrhythmic Agents103.

The IKs channel blocking ability of compound 21 (293B, Figure 28) was found to be a side activity in another research program dealing precisely with cromakalim-related chromanols such as compound 20 (HOE-234). Initially it was assumed that compound 21 acts indirectly on the Cl- transport by blocking an associated cAMP-regulated potassium channel104.

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SOSA: THE NEW LEAD FROM OLD DRUGS

Figure 28. Cromakalim-derived IKs channel blockers103. Subsequent studies on cloned potassium channels from the guinea pig demonstrated that the chromanol 21 specifically blocks IKs channels expressed in Xenopus oocytes with an IC50 value of 6.2 M105. The (3R,4S)- enantiomer was found to be more potent than the (3S,4R)-enantiomer (IC50 = 5 and 39 M, respectively). Further optimization led to compound 22 (HMR-1556; IC50 120 nM) characterized by inverted stereocenters and by the replacement of the cyano function by a trifluorobutoxy side chain106. 4.4.4. Aminopyridazine Minaprine as Lead Substance. Aminopyridazines and, more precisely, 3-amino-6-arylpyridazines represent another group of privileged structures107. They present generally favorable ADME and toxicological profiles and allow many chemical variations. 4.4.4.1. Transforming the Antidepressant Minaprine into a Muscarinic M1 Receptor Ligand. In the field of pyridazine chemistry we could, starting from the antidepressant minaprine 23 (Figure 29), derive various SOSA switches. Minaprine itself, in addition to reinforcing serotonergic and dopaminergic transmission, also possesses weak affinity for muscarinic M1 receptors (Ki =17 M).

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SOSA: THE NEW LEAD FROM OLD DRUGS

Figure 29. SOSA switch from the antidepressant minaprine To a nanomolar partial agonist for muscarinicM1 receptors108,109. Three simple chemical variations (Figure 29) (shift of the methyl group from the 3- to the 4-position (2324), replacement of the morpholine by a tropane (2425), and introduction of an OH in the ortho position of the phenyl ring (2526)) abolished the dopaminergic and serotoninergic activities and boosted the partial agonistic cholinergic activity of compound 26 to nanomolar concentrations108,109. The remarkable result was that the initial activity of minaprine on the dopaminergic and serotoninergic transmission was totally abolished in the final compound 26. 4.4.4.2. Minaprine as a Source of Reversible Acetyl cholinesterase Inhibitors

Figure 30. IC50 values for acetyl cholinesterase inhibition (electric eel enzyme).110,111 Starting from the same minaprine lead, we imagined that this molecule, being recognized by the acetylcholine receptors, should also be recognized by the DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 37

SOSA: THE NEW LEAD FROM OLD DRUGS acetylcholine enzyme. It turned out that minaprine had only a very weak affinity for acetyl cholinesterase (600 M on electric eel enzyme). However, relatively simple modifications (creation of a lipophlic cationic head, increase in side chain length, and bridging of the phenyl and the pyridazinyl rings) allowed us to reach nanomolar affinities (Figure 30)110,111. 4.4.4.3. From Minaprine to CRF Antagonists.

Figure 31. Switch from the antidepressant molecule minaprine to the potent CRF receptor antagonist 34.112,113 Another interesting switch consisted of the progressive passage from

desmethylminaprine 31 to the bioisosteric thiadiazole 32 (Figure 31) and then to the bioisosteric thiazoles. Trisubstitution on the phenyl ring and replacement of the aliphatic morpholine by a pyridine led to compound 33, which exhibited some affinity for the receptor of the 41 amino acid neuropeptide corticotrophin releasing factor (CRF). Further optimization led to nanomolar CRF antagonists such as 34.112,113 4.4.5. Neuroleptic Benzamides as Leads. The following two examples illustrate a somewhat more restrictive aspect of the SOSA approach insofar as the starting drug molecules, sulpiride and clebopride, did not actually serve for the design of new and different activities. The objective here was to transform the initial, nonselective dopaminergic antagonists in subtypeselective D3 and D4 ligands.

4.4.5.1. Transforming the D2/D3 Nonselective Neuroleptic Sulpiride into a D3Selective Partial Agonist.

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SOSA: THE NEW LEAD FROM OLD DRUGS Starting from the D2/D3 nonselective neuroleptic sulpiride, we were able to end up with a selective and potent D3 receptor ligand114,115. One of the important findings was that the benzamide present in the sulpiride derivative 35 could be advantageously replaced by a naphthamide and that additional lipophilicity on the pyrrolidine nitrogen increased the potency.

Figure 32. Switch from the D2/D3 nonselective dopamine antagonist Nmethylsulpiride 35 to the D3-selective partial agonist BP 897 39. The numbers in parentheses indicate the D2/D3 affinity ratio. The first interesting compound resulting from these variations was the D 3 antagonist nafadotride 36 in which the cyano group replaced the N-methylsulfonamido group116. Nafadotride presents an excellent affinity for the D3 receptor (Ki =0.11 nM) and a D2/D3 selectivity of 9.6 (Figure 32). However, nafadotride showed very poor bioavailability in vivo and it could not be retained for clinical development. Further modifications brought us to introduce various piperazine side chains. An is given by the o-methoxyphenylpiperazine 38, characterized by the deletion of the electronattracting group in the Meta position to the carboxamido function. Surprisingly the additional deletion of the o-methoxy group, as in compound 39, led to a potent dopaminergic ligand (Ki =1.2 nM for D3) with a 56:1 preferential affinity for the D 3 receptor114. This compound, named Do 897 and later BP 897, behaves as a partial dopaminergic agonist and presently undergoes phase II clinical investigations. Potential clinical applications are the selective inhibition of cocaine-seeking behavior by drug addicts and the possible use as neuroleptic and as a means to suppress LDopa-induced dyskinesia in the treatment of Parkinson patients. 4.4.5.2. Clebopride and Nemonapride as Leads for D4-Selective Dopaminergic Antagonists117.

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SOSA: THE NEW LEAD FROM OLD DRUGS

Figure 33. Dopaminergic D4 receptor selective Benz amides derived from clebopride and nemonapride. In parallel to the search for D3 subtype ligands, studies aiming to create D4 subtypeselective agents were undertaken, also starting from benzamide drug molecules. Ohmori and co-workers118 reported on the results of modification of their potent D2/D3/D4 antagonist nemonapride (41, YM-09151-2), an analogue of clebopride (40), to generate the new benzamide (42, YM-43611) (Figure 33). Compound 42 has affinity for both D4 and D3 receptors (Ki = 2.1 and 21 nM, respectively) but with 110fold selectivity for D4 versus D2. Affinity for 1-adrenergic, -adrenergic, serotonergic, muscarinic, or histaminic receptors was weak or negligible. Interestingly this compound shows in vivo activity in the inhibition of apomorphine-induced climbing in mice, with an ED50 of 0.32 mg/kg sc. During further investigations of the benzamide series, Hidaka and co-workers 119 prepared 43 (YM-50001). This compound showed affinity for human D4 receptors (Ki = 5.62 nM) versus hD2, hD3, and other receptors.

4.4.6. Thalidomide, Diclofenac, and Captopril as Leads. The three following SOSA applications describe examples in which only slight chemical changes were needed to transform the starting drug molecule into an active compound with a different profile.

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SOSA: THE NEW LEAD FROM OLD DRUGS

4.4.6.1. Thalidomide: A Potent Inhibitor of TNF.120

Thalidomide (44, Figure 34), first synthesized as an antihistaminic in 1954, was introduced as a sedative/ hypnotic drug in 1956 but withdrawn because of its catastrophic teratogenicity121. In the early 1960s, a new use was found for thalidomide as a sedative in patients suffering from lepromatous leprosy (erythema nodosum leprosum, ENL). A rapid and noticeable improvement of the painful neuritis experienced by these patients was observed and published in 1965122. Particularly it appeared to be efficacious for the treatment of erythema nodosum leprosum, a possible complication of the chemotherapy of leprosy123. This activity was attributed to a blockade of the TNF production, and under restricted conditions (no administration during pregnancy or to any woman of childbearing age), thalidomide found a new use as immunomodulator.

Figure 34; Thalidomide and (S)- and (R)-R-methyl thalidomide Efforts have been made to develop derivatives of thalidomide that would specifically maintain the desired actions of the drug without its side effects. One approach was to separate the effects of the (R)-isomer from the effects of the (S)-isomer. However, this approach was not effective because in vivo racemization of thalidomide is very fast. Stable nonracemizable analogues of thalidomide. The (R)-isomer (Figure 34) was effectively shown to be a potent inhibitor of TNF production in certain cell lines. Further research of selective and potent thalidomide analogues seems promising120. 4.4.6.2. From the No steroidal Anti-inflammatory Drug Diclofenac to an Inhibitor of the Fibrin Transthyretine Amyloidal Formation.

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SOSA: THE NEW LEAD FROM OLD DRUGS Transthyretine (TTR) is a tetrameric protein made up of four identical subunits. In human plasma, it is the secondary carrier of thyroxin (thyroid binding globulin being the primary carrier) and the sole transporter of the retinol-binding protein -vitamin A complex. Under acidic conditions, such as found in the lyzosomes, TTR dissociates to an alternatively folded, monomeric intermediate that self assembles into amyloid fibrils. Deposition of wild-type TTR has been implicated to cause the disease senile systemic amyloidosis (SSA), whereas mutants such as V30M and L55P are connected with familial amyloid cardiomyopathy (FAC) and familial amyloid polyneuropathy (FAP). A limited screening identified the no steroidal anti-inflammatory drug diclofenac (47) as a potent inhibitor of TTR amyloid formation 124. Optimization of diclofenac (47), with the aim of preparing compounds with high inhibition capacities but also with preferential binding to TTR with regard to the other plasma proteins, yielded the 3,5-disubstituted positional isomer 48 and the substituted anthranilic acid 49125 (Figure 35).

Figure 35. Increasing the TTR amyloid inhibiting activity of the NSAID diclofenac as a result of the synthesis of positional isomers. 4.4.6.3. Captopril Yields Inhibitors of Serum Amyloid Component P (SAP).

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SOSA: THE NEW LEAD FROM OLD DRUGS Figure 36. Captopril epimer as lead for the design of serum Amyloid component P inhibitors126. A high-throughput assay for inhibitors of SAP binding to Alzheimers disease amyloid- (A) was performed by scientists from Roche on amyloid fibrils immobilized in micro titer plates and was applied to screen the in-house compound library126. Two hits were identified. The first one ( 50; IC50 = 100 M) was the S-3 epimer of captopril, and the second one (51; IC50 = 5 M) was the corresponding dimmer (Figure 36). Optimization simplified the central spacer group in removing the sensitive disulfide bond as well as the two methyl groups, thus eliminating two chiral centers. The obtained compound 52 (Ro 63-8695) shows a 900 nM affinity for its target. 4.4.7. Herbicides and Laundry Brighteners as Lead Substances. The last two examples of this perspective represent exotic versions of the SOSA approach. Effectively, they no longer deal with the optimization of side activities of drug molecules but with the optimization of the biological activities of nondrug molecules contained in libraries of various origins. One of the leads was an herbicide, and the other one was a laundry brightener. 4.4.7.1. Orally Active Nonpeptidic Endothelin-A Receptor Antagonist from Herbicides. The two initial lead structures 53 (Lu 110896) and 54 (Lu 110897) (Figure 37), initially designed as herbicides, were discovered by screening the chemical library of BASF for compounds that bind to the recombinant human ETA receptor127.

Figure 37. Optimization of the two herbicide leads 53 and 54 to the potent and Selective ETA antagonist 55127.

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SOSA: THE NEW LEAD FROM OLD DRUGS Compounds 53 and 54 bind to the ETA receptor with Ki values of 250 and 160 nM, respectively. The binding to the ETB receptor is much weaker (Ki = 3000 and 4700 nM). With the objective of enhancing the potency while simplifying the structure and, particularly, avoiding the presence of one of the two stereocenters, compound 55 was prepared127 It demonstrated high potency and selectivity (Ki(ETA) = 6 nM; Ki(ETB) = 1000 nM), was orally active in vivo, 30 mg/kg po), and showed a long duration of action127 4.4.7.2. Laundry Brightener as Starting Lead for Antiviral Compounds128 Human respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in premature babies and infants up to 6 month of age. Widespread outbreaks occur in the winter months in the northern hemisphere each year and frequently reach epidemic proportions. At least 50% of children are infected during their first exposure, and almost all have been infected by 2 years of age. During a high-throughput screen of a 20 000- compound library, a whole virus cell-based assay identified stilbene (56, Figure 38) as a potent RSV fusion inhibitor. This original lead has an interesting history. The compound was synthesized some 40 years earlier at American Cyanamids Organic Chemicals Division as part of a program to synthesize new laundry brighteners. Its antiviral activity (IC50 = 0.15 M) led to a synthetic optimizing effort that yielded the biphenyl analogue 57 (IC50 = 0.05 M).128,129

Figure 38. Laundry brightener as starting lead for antiviral compounds.

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SOSA: THE NEW LEAD FROM OLD DRUGS 4.4.8. From diuretic chlorthiazide to antihtpertensive drug diazoxide In some cases, an expirenced medicinal chemist knows that what functional group will elicit a particular effect. Chlorthiazide is antihypertensive agent that has strong diuretic effect as well.IT was known from sulphanamide side chain can give diuretic (increased urine excretion) activity. Consequently, diozoxide was prepared as antihypertensive drug without diuretic activity2.
N

Cl

NH H2NO2S O S O Cl O S O

NH

58

Chlorthiazide

59

Diazoxide

Figure 39. From diuretic lead chlorthiazide to antihypertensive diazoxide

4.5. DISCUSSION The SOSA approach appears to be an efficient strategy for drug discovery, particularly because it is based on the screening of drug molecules, and it thus automatically yields drug like hits. Before starting a costly HTS campaign, it can represent an appealing alternative. Once the initial screening has provided a hit, it will be used as the starting point for a drug discovery program. By use of traditional medicinal chemistry as well as parallel synthesis, the initial side activity is transformed into the main activity, and conversely, the initial main activity is strongly reduced or abolished. This strategy leads with a high probability to safe, bioavailable, original, and patentable analogues. 4.5.1. Safety and Bioavailability. During years of practicing SOSA approaches observed that starting with a drug molecule as lead substance in performing analogue synthesis increased notably the probability of obtaining safe, new chemical entities. In addition, most of them satisfy

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SOSA: THE NEW LEAD FROM OLD DRUGS obtaining safe, new chemical entities. In addition, most f them satisfy Lipinskis130,vebers131, Bergstoms132
and

and Wenlocks133

observation in term of

solubility. Oral bioavailability and drug likeness. 4.5.2. Patentability.

Figure 40.Phosphodiesterase inhibitor. The phosphodiesterase inhibitor 18 derived from the tranquillizer diazepam 17, is sufficiently chemically different to 17 and does not interfere with earlier patents. When a well-known drug hits a new target, there is a risk that several hundred or several thousand analogues of this molecule are already synthesized by the initial inventors and their early competitors. These molecules are usually protected by patents, or they belong already to the public domain. At first glance, a high risk of interference thus appears probable. In fact, in optimizing another therapeutic profile than the initial one, the medicinal chemist will rapidly prepare analogues with chemical structures very different from that of the original hit. As an example, a medicinal chemist interested in phosphodiesterases and using diazepam as lead will rapidly prepare compounds that are out of scope of the original patents precisely because they exhibit dominantly PDE inhibiting properties and almost no more affinity for the benzodiazepine receptor. 4.5.3. Originality. The screening of a library of several hundred therapeutically diverse drug molecules sometimes ends up with very surprising results. A nice example of unexpected findings resulting from a systematic screening is found in the tetra cyclic compound (1, BMS-192548) extracted from 2, Aspergilluss Niger WB2346 (Figure 19).

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1 2 BMS-192548 Figure 41.Unexpected CNS activity of the tetracycline analogue (1, BMS192548)131. For any medicinal chemist or pharmacologist, the similarity of this compound to the antibiotic tetracycline (1) is striking. However, none of them would a priori forecast that BMS-192548 exhibits central nervous system (CNS) activities. Actually the compound turns out to be a ligand for the neuropeptide Y receptor preparations134

3 4 Figure 42. Striking analogy between the vasodilator drug flosequinan (3) and the quinolone antibiotic norfloxacin (4)132. It seems probable that a similar emergence of a new activity occurred with flosequinan (3, Figure 20), which is a sulfoxide bioisostere of the quinolone antibiotics. This compound turned out to be a vasodilator and a cardiotonic drug that totally lost any antibiotic activity132.

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SOSA: THE NEW LEAD FROM OLD DRUGS 4.5.4. Orphan Diseases. As mentioned above, a differentiating peculiarity of this type of library is that it is constituted of compounds that have already been safely given to humans. Thus, if a compound were to hit with sufficient potency on an orphan target, there is a high chance that it could rapidly be tested in patients for proof of principle. This possibility represents another advantage of the SOSA approach.

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5. SUMMARY
The above discussed examples provide convincing evidence that, in addition to many drugs that were serendipitous drug discoveries, many others have resulted from the observed side effects, in the laboratory. In the clinics, or during their therapeutic application. Today, we possibly focus too much on single targets that are investigated invitro. Hidden treasure may be discovered by testing old chemisryagainst new targets, by systemically optimizing some side effect of known drugs, and by reducing drugs that failed because of problems in their metabolisms or hERG channel inhibition. Thus, it might well be that known drugs are much better source of lead structures for new projects than we anticipated so far, As a consequence, we will experience a successful comeback of traditional medicinal chemistry 52. The SOSA approach appears to be an efficient strategy for drug discovery, particularly because it is based on screening drug molecules and, thus, automatically yields drug-like hits. Before starting a costly HTS campaign, it can represent an attractive alternative. Once the initial screening has provided a hit, that molecule will be used as the starting point for a drug discovery program. Using traditional medicinal chemistry, as well as parallel synthesis, the initial side activity is transformed into the main activity and, conversely, the initial main activity is strongly reduced or abolished. This strategy has a high probability of yielding safe, bioavailability, original and patentable analogues. The SOSA approach can be compared with other approaches, such as hit or lead generation from known drug metabolites or the design of drug analogues, because it makes use of old drugs to generate new hits or leads. As a rule, the activities of metabolites are similar or close to the activity of the corresponding active molecule. Contrary to this, the SOSA approach is based on optimization of side activities that are totally different to the original activity of molecule53

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6. REFERENCES
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J.; Dautzenberg, F. M. High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/ Nociceptin) Receptor. J. Med. Chem. 2000, 43, 1329-1338. 11). Doman, T. N.; McGovern, S. L.; Witherbee, B. J.; Kasten, T. P.; Kurumbail, R.; Stallings, W. C.; Connolly, D. T.; Shoichet, B. K. Molecular docking and high throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J. Med. Chem. 2002, 45, 22132221. 12). Youngman, M. A.; M.; Nepomuceno, D. H.; Wilson, S. J.; Crooke, J. J.; Rosenthal, D.; Vaidya,A. H.; Dax, S. L. N -(Sulfonamido)-alkyl--aminotetralins: Potent and Selective Neuropeptide Y Y5 Receptor Antagonists. J. Med. Chem. 2000, 43, 346-350 13). Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson, R. J.; Doubleday, R.; Unangst, P. C.; Roth, B. D.; Beylin, B. G.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.; Bornemeier 1161-1169. D. A.; Dyer, R. D. Synthesis, Structure-Activity Relationships and in Vivo Evaluations of Substituted Di-tert-butylphenols as a Novel Class of Potent, Selective, and Orally Active Cyclooxygenase-2 Inhibitors. 2. 1,3,4- and 1,2,4-Thiadiazole Series. J. Med. Chem. 1999, 42, 14). Gilligan, P. J.; Robertson, D. W.; Zaczek, R. Corticotropin Releasing Factor (CRF) Receptor Modulators: Progress and Opportunities for New Therapeutic Agents. J. Med. Chem. 2000, 43, 1641-1660. 15). Baxter, A.; Bennion, C.; Bent, J.; Boden, K.; Brough, S.; Cooper, A.; Kinchin, E.; Kindon, N.; McInally, T.; Mortimore, M.; Roberts, B.; Unitt, J. Hit-to-Lead Studies: The Discovery Of Potent, Orally Bioavailability, Triazolethiol CXCR2 Receptor Antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 2625-2628. McNally, J. J.; Lovenberg, T. W.; Reitz, A.B.; Willard, N.

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dthydropyridine derivative with anti-calmodulin activity in the mammal tumor cell line ZR75-1. Med. Sci. Res. 1990, 18, 627-629. 78). Fiebig, H. H.; Berger, D. P.; Dengler, W.; Licht, T.; Winterhalter, B.; Wallbrecher, E.; Sanders, K. H. B859-35, a new anticancer drug with MDR reversing properties. Ann. Oncol. 1992, 3 (Suppl.1), 52. 79). Gekeler, V.; Wilisch, A.; Engelcke, M.; Probst, G.; Hofmann, J.; Neumann, M.; Probst, H. Effects of the new PKC inhibitor dexniguldipine-l-ICI (B859-035), an enantiomeric pure dihydropyridine, on DNA-replication and cell cycle. Proc. Am. Assoc. Cancer Res. 1993, 34, 2439. 80). Ukena, D.; Boewer, C.; Oldenkott, B.; Rathbeg, F.; Wurst, W.; Zech, K.; Sybrecht, G. W. Tolerance, safety, and kinetics of the new antineoplastic compound dexniguldipine-HCI after oral administration. A phase I dose-escalation trial. Cancer Chemother. Pharmacol. 1995, 36, 160-164. 81). Basil, B.; Coffee, E. C. J.; Gell, D. L.; Maxwell, D. R.; Sheffield, D. J.; Wooldridge, K. R. H. A New Class of Sympathic -Receptor Blocking Agents. 3,4-Dihydro-3-hydroxy-1,5benzoxazocines. J.Med. Chem. 1970, 13, 403-406. 82). Greenwood, D. T.; Mallion, K. B.; Todd, A. H.; Turner, R. W. 2-Aryloxymethyl-2,3,5,6tetrahydro-1,4-oxazines, a new class of antidepressants. J. Med. Chem. 1975, 18, 573577. 83). Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.; Watts, E. A. Synthesis and Antihypertensive Activity of Substituted trans-4-Amino-3,4-dihydro-2,2-dimethyl-2H-1benzopyran-3-ols. J. Med. Chem. 1983, 26, 1582-1589. 84). Evans, J. M.; Fake, C. S.; Hamilton, T. C.; Poyser, R. H.; Showell, G. A. Synthesis and Antihypertensive Activity of 6,7-Disubstituted trans-4-Amino-3,4-dihydro-2,2-dimethyl2H-1-benzopyran- 3-ols. J. Med. Chem. 1984, 27, 1127-1131. 85). Stemp, G.; Evans, J. M. Discovery and Development of Cromakalim and Related Potasssium Channel Activators. Medicinal ChemistrysThe Role of Organic Chemistry in Drug Research, 2nd ed.; Academic Press: London, 1993; pp 141-162. 86). Gerlach, U. IKs channel blockers: potential antiarrhythmic agents. Drugs Future 2001, 26, 473-484.

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