sidhu thesis
TRANSCRIPT
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 computer-
assisted 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 drug–receptor
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.
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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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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.
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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
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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 screening). It is by such an approach that the
antihistaminic, and later on the neuroleptic properties of the amines
derived from phenothiazine, were identified. Initially these
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
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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 hydroxymethyl- Glutaryl-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 screening is usually applied to the
displacement of radioligands and to the inhibition of enzymes. The
present trend is to replace radioligand-based assays by
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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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 low-
quality 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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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 side effects
constitutes a quasi in exhaustible source of tracks in the search
for lead compounds. Indeed, besides the
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
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the activity originally considered as secondary and diminish or
cancel the activity that was initially dominant. Promethazine, for
example, an antihistaminic derivative of phenothiazine, has
important sedative effects. Like Laborit et al., 21 a clinician might
promote the utilization of this side-effect and direct research
towards better-profiled analogues.
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, the antidepressant effect of isoniazid, an
antitubercular drug, and the hypotensive effect of β-blocking
agents.
Figure 5: The clinical observation of the hypotensive Activity of the ‘open’ (and therefore flexible) β-blocking of β-blocking activity, but retaining the antihypertensive activity.23
This last example is beautifully illustrated by the discovery of the
potassium channel activator cromakalin.23 Cromakalin is the first
antihypertensive agent shown to act exclusively through
potassium channel activation.24 This novel mechanism of action
involves an increase in the outward movement of potassium ions
through channels in the membranes of vascular smooth muscle
cells, leading to relaxation of the smooth muscle. The discovery of
this compound can be summarized as follows: β-Adrenergic
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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 otherβ-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 β-blocking molecules, to dissociate the β-blockade from
the antihypertensive activity.
Among the various conceivable molecular variations which are
possible for the flexible β-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
β-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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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 known as the Wolff-Parkinson-White syndrome.
Accordingly, amiodarone was reintroduced specifically for that
purpose.28
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, was specifically marketed for its uricosuric
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
. Figure 7: Structure of thalidomide. The marketed compound is the racemate.
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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
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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 dicoumarol-
derived 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
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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 anti-
Parkinson 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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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.
Figure 10: ASS 1 is much more than prodrug of salicylic acid. It’s 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.
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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Figure 14
The aniline-imidazoline clonidine 17 (Catapresan, boehringer ingelheim;figure
14 )
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 s-
1 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.
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
of its antidepressant activity52.Later it was withdrawn from therapy ,due to
hepatotoxic side effect.
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Figure 16
D-Penicillamine 20 (figure 16) has for long time been used for the treatment of
Wilson’s 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.
Figure 17
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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 xanthine derivatives. Their first leads 21
and 22 (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 PDE5-
selective 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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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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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 available61. 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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Compounds as different as benzyl penicillin or D-tubocurarine unexpectedly
shows micro molar affinity for GABA-A receptors66.
N-α-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 master’s 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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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 ETA
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 µM). Testing of
related sulfonamides identified the more potent sulfisoxazole 2 (ETA
IC50 = 0.78 µM). 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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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 BMS-207940.71,72
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 (BMS-
207940, 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 µg/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
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Karmazyn in 198874 where it was shown that amiloride 6 (Figure 22), a potassium-
sparing 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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for the synthesis of α1A-adrenergic antagonists and of multi drug-resistance
modulators.
4.4.2.1. Calcium Channel Blocker Niguldipine as a Source of α1A-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 α –reductase inhibitors such as finasteride are used to reduce the prostatic mass, α1-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 α1A-Adrenergic antagonist 14 (SNAP-6383)81.
However, nonselective α1-adrenergic receptor antagonists present cardiovascular side
effects (tachycardia and orthostatic hypotension). Selective blockers of the α1A-
subtype 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 α1A-adrenoceptor (Figure 23). Moreover, niguldipine presents
considerable α1A -selectivity (>300-fold over α1B- and α1D-receptors. Niguldipine was
developed as a racemate; however, the α1-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 Phe-
312 in the transmembrane domain 7 of the α1A-receptor results in significant losses of
affinity (4- to 1200-fold) for the antagonists prazosin, WB4101, BMY7378, (S)- (+)-
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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 α1A-receptor subtype, which correlates well with the potency to
inhibit the phenylephrine induced contraction of dog prostate. Compound 14 binds to
the human recombinant α1A 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 isozyme-
mediated metabolism and the corresponding risk of drug-drug interaction81.
Figure 24. Monatepil maleate (15) combines calcium channel blocking activity, α1-adrenoceptor antagonism, and inhibition Of lipid hydroperoxidation.84,86
A similar finding associating calcium channel blocking activity with α1-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
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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 P-
glycoprotein90, 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 P-
glycoprotein, 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 channels86 and
shows promise as a reverser of multidrug resistance86. It only has 1/40 the affinity for
the L-type calcium channel as its enantiomer, niguldipine91. 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 β -Blockers.
Conventional β-blockers possess a number of pharmacological properties, e.g., β-
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 β-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
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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 β-receptors.
Figure26. Cyclized analogues of β-blocking phenylpropanolamines.98,99,102
Attempts to exploit the sedative and anticonvulsant effects observed for propranolol
in pharmacological experiments prompted Greenwood et al99. 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 β-blockers. The authors
hoped that by restricting the conformation, β-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 β-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 β-blockers such as atenolol102. β-
Blockers were introduced in the early 1970s for the treatment of angina pectoris and
hypertension. However, there was some doubt that β-blockade was responsible for
their antihypertensive activity and it was suggested that analogues with reduced
flexibility of the side chain may be devoid of β-blocking activity but would retain the
antihypertensive activity. This was the initial lead to cyclized analogues (Figure 27).
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Figure 27. Passage from “open- β-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
β-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; β-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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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 µM105. The (3R,4S)- enantiomer was found to be more potent
than the (3S,4R)-enantiomer (IC50 = 5 and 39 µM, 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 µM).
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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 (23→24), replacement of the morpholine by a tropane (24→25), and
introduction of an OH in the ortho position of the phenyl ring (25→26)) 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
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acetylcholine enzyme. It turned out that minaprine had only a very weak affinity for
acetyl cholinesterase (600 µM 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 subtype-
selective D3 and D4 ligands.
4.4.5.1. Transforming the D2/D3 Nonselective Neuroleptic Sulpiride into a D3- Selective Partial Agonist.
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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 N-methylsulpiride 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 D3 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 electron-
attracting 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 D3
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 L-
Dopa-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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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 subtype-
selective 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 110-
fold selectivity for D4 versus D2. Affinity for α1-adrenergic, β-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-workers119
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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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.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 40
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 formation124. 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”).
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 41
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 Alzheimer’s disease
amyloid-β (Aβ) 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 µM) was the S-3
epimer of captopril, and the second one (51; IC50 = 5 µM) 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 andSelective ETA antagonist 55127.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 42
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 Cyanamid’s Organic Chemicals Division as part of a
program to synthesize new laundry brighteners. Its antiviral activity (IC50 = 0.15 µM)
led to a synthetic optimizing effort that yielded the biphenyl analogue 57 (IC50 =
0.05 µM).128,129
Figure 38. Laundry brightener as starting lead for antiviral compounds.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 43
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.
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
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 44
SOSA: THE NEW LEAD FROM OLD DRUGS
obtaining safe, new chemical entities. In addition, most f them satisfy
Lipinski’s130,veber’s131, Bergstom’s132 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, Aspergillus’s Niger WB2346 (Figure 19).
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 45
SOSA: THE NEW LEAD FROM OLD DRUGS
1 2 BMS-192548
Figure 41.Unexpected CNS activity of the tetracycline analogue (1, BMS-192548)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.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 46
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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.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY 47
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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 chemisry’against 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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