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Drug Discovery by Design

Gareth Thomas


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2.1. Introduction

Drug discovery is part luck and part structured investigation. At the beginning of the nineteenth century it was largely carried out by individuals but it now requires teamwork, the members of the team being specialists in various fields, such as medicine, biochemistry, chemistry, computerised molecular modelling, pharmaceutics, pharmacology, microbiology, toxicology, physiology and pathology.
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lead compounds

drugs used in medicine are developed from so-called lead compounds (Figure 2.1). These compounds were originally discovered by investigating local folk remedies, and natural products such as plants (land and marine), trees, microorganisms and animals.
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Local folk remedies

Natural products
Lead compounds
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These are still useful sources of lead compounds but many are now produced as a result of investigations into the nature of disease states. Lead compounds are often unsuitable for clinical use because they may be

either too toxic or have serious unwanted side effects.

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However, their structures serve as the starting points for the synthesis of socalled analogues, one or more of which may be suitable for clinical use (Figure 2.1).


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The approach to drug design

the objectives of the design team. These objectives can range from changing the pharmacokinetics of an existing drug to designing a completely new compound. In all cases the team will start by devising an outline of the intended investigation.

The approach to drug design depends on


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For example, if the objective is to modify the pharmacokinetics of an existing drug the design team has to decide what structural modifications need to be investigated in order to achieve that objective.


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On the other hand, if the objective is to find a new drug for a specific medical problem the starting point is a knowledge of the biochemistry of the condition and/or the microorganism responsible for the condition.


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This may require basic research into the disease-causing process before initiating the drug design investigation (Figure 2.1). The information obtained is used by the team to decide where intervention would be most likely to bring about the desired result. Once the point of intervention has been selected the team has to decide on the

structure of a lead compound that could possibly bring about the required change.


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Objective Drug disign

Modify the pharmacokinetic of an existing drugs What structural modification need to be investigated

Designing a completely new compound

Disease causing process The structure of LC that could be changed
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Compound analog

A number of candidates are usually considered but the expense of producing drugs dictates that the team has to choose only one or two of these compounds to either act as the lead or to be the inspiration for the lead compound. The final selection depends on the experience of the team.

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One approach to lead compound selection is to carry out a comprehensive literature and database search to identify compounds found in the organism (endogenous compounds) and compounds that are not found in the organism (exogenous compounds) that have some biological effect at the intervention site. These compounds are used as leads and modified in an appropriate manner.
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Lead Compound selection

Endoge nous compou nd

Neurotransmiter Ezyme Hormone

Exogen ous compou ns

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Secondary Metabolite Minerale



Figure 2.1. The general steps in the design of a new drug.

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Modern approaches to lead compound discovery include combinatorial

chemistry and computer modeling techniques .

The former uses a simultaneous multiple synthesis technique to produce large numbers of potential leads. These potential leads are subjected to rapid high-throughput biological screening to identify the most active lead compounds.
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Once identified, these lead compounds are subject to further development. Computer modeling is normally used to check

whether the three-dimensional structure of the proposed lead is complementary to that of its receptor domain.
However, this does require a detailed knowledge of the three-dimensional structures of the ligand and target site.
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enantiomers and their racemates

A major consideration in the selection of a lead is its stereochemistry. It is now recognised that the biological activities of the individual enantiomers and their racemates may be very different. Consequently, it is necessary to evaluate pharmacologically the individual enantiomers as well as any racemates.

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However, it is often difficult to obtain specific enantiomers in a pure state. Both of these considerations make the production of optically active compounds expensive and so medicinal chemists

often prefer to synthesis lead compounds that are not optically active.
However, this is not always possible.


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Once the structure of the proposed lead has been decided it becomes the responsibility of the medicinal chemist to devise a synthetic

route and prepare a sample of this compound for testing.

Once synthesised, the compound undergoes initial pharmacological and toxicological testing. The results of these tests enable the team to decide whether it is profitable to continue development by preparing analogues (Figure 2.1) because it is unlikely that the lead compound It self will he suitable for use as a drug.
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The usual scenario is to prepare a series of analogues and analyse the results of their biological testing to determine the structure with optimum activity. This analysis may make use of SAR ,QSAR , computational chemistry, and combinatorial chemistry, to help discover the nature of this structure.


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The selection of a lead compound and the development of a synthetic pathway for its preparation is not the only consideration at the start of an investigation. It is no use preparing a series of compounds if there is no suitable

testing procedure.


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Researchers must also devise suitable in vivo and in vitro tests to assess the activity and toxicity of the compounds produced. There is no point in carrying out an expensive synthetic procedure if at the

end of the day it is impossible to test the product.

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The processes of drug discovery outlined in this section are time

consuming and expensive.

It takes about 10 years for a drug to reach the general public and only one in about 10000 of the compounds prepared is ever used.


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2.2 Stereochemistry and Drug Design It is now well established that the shape of a molecule is normally one of the most important factors that affect drug activity. Consequently, the overall shape of the structure of a molecule is an important consideration when designing an analogue. Some structural features impose a considerable degree of rigidity into a structure whereas others make the structure more flexible.

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structures give rise to stereoisomers that can exhibit

different potencies, types of activity and unwanted side effects.


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It is necessary to consider all these stereochemical features in the design of a potential analogue. However, the extent to which one can exploit these structural features will depend on our knowledge of the

structure and biochemistry of the target biological system.

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2.2.1 Structurally Rigid Groups

Groups that are structurally rigid are

former include esters and amides as well as aliphatic conjugated systems and aromatic and heteroaromatic ring systems. The binding of these rigid structures to a target site can give information about the shape of that site as well as the nature of the interaction between the site and the ligand.
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unsaturated groups of all types and saturated ring systems (Figure 2.2). The


Aliphatic conjugatisc systems

Structurally rigid compond Compound Structurally flexible compound

Aromatic sytems
Heteroaromatic systems


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Rigid structures

Rigid structures may also be used to determine the conformation assumed by a ligand when it binds to its target site. Furthermore, the fact that the structure is rigid means that it may be replaced by

alternative rigid structures of a similar size and shape to form analogues that may have
different binding characteristics and possibly, as a result, a different activity or


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Figure 2.2. Examples of structural groups that impose a rigid shape on sections of a molecule. The shaded areas represent the rigid sections of the molecule.
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2.2.2. Conformation
Early work in the 1950s and early 1960s by Schueler and Archer suggested that the flexibility of the structures of both ligands and receptors accounted for the same ligand being able to bind to different subtypes of a receptor. Archer also concluded that a ligand appeared to assume different conformations when it bound to the different subtypes of a receptor.

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example, acetylcholine exhibits both muscarinic and nicotinic



and collegues suggested that the muscarinic activity was

due to the anti or staggered conformation whereas the nicotinic activity was due to the syn or eclipsed form (Figure 2.3).
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Figure 2.3. Syn and anti conformers of acetylcholine and 2-tropanyl ethanoate methiodides.
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These workers based this suggestion on their observation that the anti conformation of 2-tropanyl ethanoate methiodides preferentially binds to muscarinic receptors whereas the syn

conformation binds preferentially to nicotinic receptors.


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The structures of both of these compounds contain an acetylcholine residue locked in the appropriate conformation by the ring structure. This and subsequent investigations led to the conclusion that the development of analogues

with restricted or rigid conformations could result in the selective binding of drugs to target sites that could result in very active drugs with reduced unwanted side effects.
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steric hindrance will prevent the binding

The main methods of introducing conformational restrictions are by using bulky substituents, unsaturated structures or small ring systems. Small ring systems are usually the most popular choice (Figure 2.4). In all cases the structures used must be chosen with care because there will always be the possibility that steric hindrance will prevent the binding of the analogue to the target
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Figure 2.4. Examples of the use of conformational restrictions to produce analogues of (a) histamine and (b) do amine Bonds marked with an asterisk can exhibit free rotation and form numerous conformers.
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However, if sufficient information is available. Computer modeling can be of considerable assistance in the choice of structures. A further limitation is knowing which bond to restrict. Even in simple molecules numerous eclipsed, staggered and gauche conformations are possible (Figure 2.5).

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Figure 2.5. Examples of some of the major conformations of the C1-C2 bond of acetylcholine. Other conformations occur about the C-N and C-O single bonds.


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The biological data obtained using restricted conformation analogues can be of use in determining the most bioactive conformation of the ligand. If the analogue exhibits either the same or a greater degree of activity as the lead compound it max be concluded

that the analogue has the correct conformation for binding to that site.
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However, if the analogue exhibits no activity the result could he due to either : steric hindrance between the restricting group and the target or the analogue having the incorrect conformation. In this case computer modeling may be of some assistance.

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2.2.3 Configuration

Configurational centres impose a rigid

However, their presence gives rise to geometric and optical isomerism. Because these stereoisomers have different shapes, biologically active stereoisomers will often exhibit differences in their potencies and/or activities (Table 2.1).

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shape on sections of the molecule in which they occur.


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Table 2.1. Variations in the biological activities of stereoisomers.

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These pharmacological variations are particularly likely when a chiral centre is

located in a critical position in the structure of the molecule.

The consequence of these differences is that it is now necessary to make and test separately all the individual stereoisomers of a drug.
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As well as an effect on the activity, different stereoisorners will also change other physiochemical properties such as absorption,

metabolism and elimination.

For example, (-)-norgestrel is absorbed at twice the rate of (+)-norgestrel through buccal and vaginal membranes. The plasma half-life of S-indacrinone is 2-5h whereas the value for the R isomer is 1012 h.
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2.3. Structure-Activity Relationships (SAR)

Most drugs act at a specific site such as an enzyme or receptor. Compounds with similar structures often tend to have similar pharmacological activity. However, they usually exhibit

differences in potency and unwanted side effects and in some cases

different activities.

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These structurally related differences are commonly referred to as structure activityrelationships (SAR). A study of the structure-activity relationships of a lead compound and its analogues can be used to determine the parts

of the structure of the lead that are responsible for its biological activity, that is, its pharmacophore and also its unwanted side
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This information is subsequently used to develop a new drug that has increased activity (optimise its SAR). A different activity from an existing drug, fewer unwanted side effects and improved ease of administration to the patient.


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Structure-activity relationships are usually determined by making minor

changes to the structure of the lead and assessing the effect that this has on biological activity.

Traditional SAR investigations are carried out by making large numbers of analogues of the lead and testing them for biological activity.
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Over the years numerous lead compounds have been investigated and from the mass of data it is possible to make some broad generalisations about

the biological effects of specific structural changes.


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These changes may be conveniently classified as:


the size and shape of the carbon skeleton. (2) the nature and degree of substitution, and (3) the stereochemistry of the lead.
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selection of the changes required to produce analogues of a particular lead is made by

considering the activities of compounds with similar structures

and also the possible chemistry and biochemistry of the intended analogue.
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For example

replacing a hydroxy group with a methyl group could reduce the water solubility of the analogue and also its ability to hydrogen bond. The former could reduce its ease of absorption whereas the latter could affect its ability to bind to its target site. It could improve the transport of the drug through membranes and also introduce changes in the metabolism of the drug.
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For example,
oxidation of the methyl group to a carboxylic group could increase the rate of metabolism. All these effects could result in a loss of activity or a reduction in an unwanted side effect. A further consideration is the size of the analogue. Changing the structure of the lead could result in an analogue that is too big to fit its intended target site.

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Computerised molecular modeling can be used to check this provided that the structure of the target is known or can he simulated with some degree of accuracy. Traditional SAR investigation procedures are useful tools in the search for new drugs.


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However, they are expensive in both personnel and materials. Consequently, a number of attempts have been made to improve on traditional structureactivity investigations with varying degrees of success .


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2.3.1 Changing Size and Shape

The shapes and sizes of molecules can be modified in a variety of ways, such as: (i) changing the number of methylene groups in chains and rings: (ii) increasing or decreasing the degree of unsaturation: (iii) introducing or removing a ring



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60 Changing the Number of Methylene Groups in a Chain

Increasing the number of methylene groups in a chain or ring increases the

of the compound. The biological response curves associated with this increase in size can assume a variety of shapes (Figure 2.6a).
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size and the lipid nature (lipophilicity)

It is believed that the increase in activity with increase in the number of methylene groups is probably due to an increase in the

lipid solubility of the analogue, which gives a better membrane penetration. Conversely, a decrease in activity (Figure

2.6b) with an increase in the number of methylene groups is attributed to a reduction in the water solubility of the analogues.
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Figure 2.6. Examples of the variation of response curves with increasing numbers of inserted meth1ene groups. (a) A study by Dohme and collegues on the variation of antibacterial activity of 4-a]kyl-suhstituted resorcinols. (h) Inhibition of angiotensinconverting enzyme by enalaprilat analogues (Thorseti). The values in parentheses are 11/7/2013 prof. aza 63 IC50 values for those analogues.

This reduction in water solubility can result in the poor distribution of the analogue in tile aqueous media as well as

the trapping of the analogue in biological membranes .


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micelle formation
A further problem with large increases in the numbers of inserted methylene groups in chain structures is micelle formation . Micelle formation produces large aggregates that, because of their shape, cannot bind to active sites and receptors.

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have an effect on the potency and type of activity of analogues. For example, the replacement of the sulphur atom of the antipsychotic chlorpromazine by CH2-CH2- produces the antidepressant clomiprarnine.
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Introducing chain branching, different sized rings and the substitution of chains for rings and vice versa may also Changing the Degree of Unsaturafion


removal of double bonds increases the degree of flexibility of the molecule, which may make it
up a more suitable conformation. However, an increase in flexibility

easier for the analogue to fit into active and receptor sites by taking could also result in a change or loss of activity.
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The introduction of a double bond increases the rigidity of the structure. It may also introduce the complication of E- and Zisomers, which could have quite different activities (see Table 2.1). The analogues produced by the introduction of unsaturated structures into a lead compound may exhibit different degrees of

potency or different types of activities

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For example, the potency of prednisone

does not have a 1-2 C=C bond. The replacement of the S atom of the antipsychotic phenothiazine drugs by a CH=CH- group gives the antidepressant dibenzazepine drugs, such as protriptyline.
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is about 30 times greater than that of its parent compound cortisol, which


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The introduction of a C=C group will often give analogues that are more

sensitive to metabolic oxidation.

This may or may not be a desirable feature for the new drug. Furthermore, the reactivity of C=C frequently causes the analogue to be more toxic than the


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71 Introduction or Removal of a Ring System The introduction of a ring system changes the shape and increases the overall size of the analogue. The effect of these changes on the potency and activity of the analogue is not generally predictable. However, the increase in size can be useful in filling a hydrophobic pocket in a target site, which might strengthen the binding of

the drug to the target.

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For example

it has been postulated that the increased inhibitory activity of the cyclopentyl analogue (rolipram) of 3(3,4-dimethyloxyphenyl)-butyrolactam towards cAMP phosphodiesterase is due to the cyclopentyl group filling a hydrophobic pocket in the active site of this enzyme.
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The incorporation of smaller, as against larger, alicyclic ring systems into a lead structure reduces the possibility of producing an analogue that is too big for its target site. It also reduces the possibility of complication caused by tile existence of conformers. However. the selection of the system for a particular analogue may depend on the objective of the alteration.
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For example,

replace this group if a more stable compound of a similar size is required. For example, the antidepressant tranylcypromine is more stable than its analogue 1 -amino-2phenylethene.
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cyclopropane ring is usually more stable than the ethylenic C=C group and so could be used to


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insertion of aromatic systems into the structure of the lead will introduce rigidity into the structure as well as increase the

aromatic systems


size of the analogue.

latter means that small aromatic systems such as benzene

and five-membered heterocyclic sytems are often preferred to

larger systems.
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However, the electrons of aromatic systems may or may not improve the

binding of the analogue to its target site.

Furthermore, heterocyclic aromatic systems will also introduce extra

functional groups into the structure,

which could also affect the potency and activity of the analogue.
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For example,

the resistance of diphenicillin to -lactamase is believed to be due to the diphenyl group

preventing the enzyme from reaching the

lactam. It is interesting to note that 2phenylhenzylpenicillin is not resistant to lactamase attack. In this case, it appears that the diphenyl group is too far away from the -lactam ring to hinder the attack of the lactamase.
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For example,
replacement of the N-dimethyl group of chlorpromazine by an Nmethylpiperazine group produces an analogue (prochlorperazine) with increased antiemetic potency but reduced neuroleptic activity. It has been suggested that this change in activity could be due to
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the presence of the extra tertiaryamine group.



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incorporation of ring systems, especially larger systems, into the structure of a lead can be used to produce analogues that are resistant to enzymic attack by

sterically hindering the access of the enzyme to the relevant functional group.
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For example,
the resistance of diphenicillin to -lactamase

is believed to be due to the diphenyl group

preventing the enzyme from reaching the lactam.

It is interesting to note that 2phenylbenzylpenicillin is not resistant to lactamase attack. In this case, it appears that

the diphenyl group is too far away from the -lactam ring to hinder the attack of the lactamase.
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of the potent pharmacologically active naturally occurring compounds, such as the alkaloids morphine and curare, have such complex structures that it would not be economic to synthesise them on a large scale. Furthermore, they also tend to exhibit unwanted side effects.
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However, the structures of many of these compounds contain several ring systems. In these cases, one approach to designing analogues of these compounds centres around

determining the pharmacophore and removing any surplus ring structures. It is hoped that
this will also result in the loss of any unwanted side effects. The classic example illustrating this type of approach is the development of drugs from morphine (Figure 2.7).
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It is hoped that this will also result in the loss of any unwanted side effects. The classic example illustrating this type of approach is the development of drugs from morphine (Figure 2.7).


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Figure 2.7. The pharmacophore of morphine was found to be the structure represented by the bonds in heavy type. Pruning and modification of the remaining structure of morphine resulted in the developmcnt of (a) the more potent but still highly addictive levorphanol, (b) the very much less potent pethidine, (c) the less potent and less addictive pentazocine and (d) the equally potent but much less addictive methadone, amongst other drugs.
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2.3.2 Introduction of New Substituents


formation of analogues by the introduction of new substituents into the structure of a lead may result in an

analogue with significantly different chemical and hence pharmacokinetic properties.

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For example, the introduction of a new substituent may cause significant

membranes and the various fluids found in the body. It would also change the shape, which could result in conformational restrictions that affect the binding to the target site.
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changes in lipophilicity that affect transport of the analogue through

the presence of a new group In addition, the presence of a new group may introduce a new metabolic pathway for the analogue. These changes will in turn affect the pharmacodynamic properties of the analogue. For example, they could result in an analogue with either increased or

decreased potency, duration of action, metabolic stability and unwanted side effects.
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The choice of substituent will depend on the properties that the development team decide to enhance in an attempt to meet their objectives. Each substituent will impart its own characteristic properties to the analogue. However, it is possible to generalise about the effect of introducing a new substituent group into a structure but there will be numerous exceptions to the predictions.

11/7/2013 prof. aza 94 Methyl Groups

The introduction of methyl groups usually increases the lipophilicity of the compound and reduces its water solubility (Table 2.2). It should improve the ease of absorption of the analogue into a biological membrane ,but will make its release from biological membranes into the aqueous media more difficult.

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Table 2.2. The change in the partition coefficients (P) of some common compounds when methyl groups are introduced into their structures.

The greater the value of P the more lipidsoluble the compound. Benzene and toluene values were measured using an noctanol/water system and the remaining values were measured using an olive oil/water system.
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incorporation of a methyl group can impose steric restrictions on the structure of an analogue. For example, the ortho-methyl analogue of diphenhydramine exhibits no antihistamine activity.


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Ortho/para subtituent

Harmes and collegues suggest that this could be due to the ortho-methyl group

molecule from adopting the conformation necessary for antihistamine activity. It is interesting to note that the paramethyl analogue is 3.7 times more active than diphenhydramine.
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restricting rotation about the C-O bond of the side chain. This prevents the


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The incorporation of a methyl group

can have one of three general effects on the rate of metabolism of an analogue: (i) an increased rate of metabolism due to oxidation of the methyl group; (ii) an increase in the rate of metabolism due to demethylation by the transfer of the methyl group to another compound; or a reduction in the rate of metabolism of the analogue.
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(i) A methyl group bound to an aromatic ring or a structure which increases its reactivity may be metabolised to a carboxylic acid, which can be eliminated more easily. (ii) For example, the antidiabetic tolbutamide is metabolised to its less toxic benzoic acid derivative. The introduction of a reactive C-CH group offers a detoxification route for lead compounds that are too toxic to be of use.
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associated with carcinogenic action

(ii) Demethylation is more likely to occur

when the methyl group is attached to

methyl group attached to a nitrogen, oxygen or sulphur atom to act in this manner. A number of methyl transfers have

positively charged nitrogen and sulphur atoms, although it is possible for any

been associated with carcinogenic action.

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(iii) Methyl groups can reduce the rate

giving the analogue a slower rate of metabolism than the lead. For example, the action of the agricultural fungicide nabam is due to it being metabolised to the active diisothiocyanate. N-Methylation of

of metabolism of a compound by masking a metabolically active group, thereby

nabam yields an analogue that is inactive

because it cannot be metabolised to the active diisothiocyanate.
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Methylation can also reduce the unwanted side effects of a drug. For example, mono- and diorthomethylation with respect to the phenolic hydroxy group of paracetamol produce analogues with reduced


It is believed that this reduction is due to the methyl groups preventing metabolic hydroxylation of these ortho positions.
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methyl and ethyl groups

Larger alkyl groups will have similar effects. However, as the size of the group increases, the lipophilicity will reach a point where it reduces the water solubility to an impractical level. Consequently, most substitutions are restricted to methyl and ethyl groups.

11/7/2013 prof. aza 109 Halogen Groups

The incorporation of halogen atoms into a lead results in analogues that are more lipophilic and so less water soluble. Consequently, halogen atoms are used to

improve the penetration of lipid membranes.

However, there is an undesirable tendency for halogenated drugs to

accumulate in lipid tissue.

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The chemical reactivity of halogen atoms depends on both their point of attachment to the lead and the nature of the halogen.

Aromatic halogen groups are far less reactive than aliphatic halogen groups,

which can exhibit considerable chemical reactivity.


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For aliphatic carbon-halogen bonds the C-F bond is the strongest and usually less (more?) chemically reactive than aliphatic C-H bonds. The other aliphatic C-halogen bonds are weaker, their reactivity increasing down the periodic table. They are usually more chemically reactive than aliphatic C-H bonds.

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the most popular halogen substitutions are the less reactive aromatic fluorine and chlorine groups. However, the presence of electronwithdrawing ring substituents may increase their reactivity to unacceptable levels.
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Trifluorocarbon groups (-CF3) are some-times used to replace chlorine because these groups are of a similar size. These substitutions avoid introducing a very reactive centre and hence a possible site for unwanted side reactions into the analogue. For example, the introduction of the more reactive bromo group can cause the drug to act as an alkylating agent.
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The changes in potency caused by the introduction of a halogen or halogencontaining group will, as with substitution by other substituents, depend on the position of the substitution. For example, the antihypertensive clonidine with its o,o-dichloro substitution is more potent than its p,m-dichloro analogue. It is believed that the bulky o-chlorine groups impose a conformational restriction on the structure of clonidine, which probably accounts for its increased activity.
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For example, the antihypertensive clonidine with its o,o-chloro substitution is more potent than its p,m-dichloro analogue. It is believed that the bulky o-chlorine

groups impose a conformational restriction on the structure of clonidine, which probably accounts for
its increased activity.
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117 Hydroxy Groups

hydrophilic nature and a lower lipid solubility. It also provides a new centre for hydrogen bonding, which could influence

The introduction of hydroxy groups in to the structure of a lead will normally produce analogues with an increased

the binding of the analogue to its target site.

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For example, the ortho-hydroxylated minaprine analogue binds more effectively to M1-muscarinic receptors than many of its non-hydroxylated analogues.


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The introduction of a hydroxy group also introduces a centre that, in the

case of phenolic groups, could act as a bacterioside whereas alcohols have narcotic properties.

However, the presence of hydroxy groups opens a new metabolic pathway that can either act as a detoxification route or prevent the drug from reaching

its target.

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120 Basic Groups

The basic groups usually found in drugs are amines, including some ring nitrogen atoms amidines and guanidines. All these basic groups can form salts in biological media. Consequently, incorporation of these basic groups into the structure of a lead will produce analogues that have a lower lipophilicity but an increased water solubility .

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This means that the more basic an

analogue, the more likely it will form salts and the less likely it will be transported through a lipid membrane.


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The introduction of basic groups may increase the binding of an analogue to its target by hydrogen bonding between that target and the basic group (Figure 2.8a). However, a number of drugs with basic groups owe their activity to salt formation and the enhanced binding that occurs due to the ionic bonding

between the drug and the target

(Figure 2.8).
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For example. it is believed that many local anaesthetics are transported to

salts which bind to the appropriate receptor sites. The incorporation of aromatic amines into the structure of a lead is usually avoided because aromatic amines are

their site of action in the form of their free bases but are converted to their

often very toxic and are often carcinogenic.

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Figure 2.8. Possible sites of (a) hydrogen bonding between a target site and amino groups and (b) ionic bonding between amine salts and a target site.
11/7/2013 prof. aza 125 Carboxylic and Sulphonic Acid Groups The introduction of carboxylic acid groups into small lead molecules may produce analogues that have a very

different type of activity or are inactive.

For example, the introduction of a carboxylic acid group into phenol results in the activity of the compound changing from being a toxic antiseptic to the less

toxic anti-inflammatory salicylic acid.

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Similarly, the incorporation of a

carboxylic acid group into the sympathomimetic phenylethylamine gives phenylalanine, which has no sympathomimetic activity.
However, the introduction of carboxylic acid groups appears to have less effect on the activity of large molecules.
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Sulphonic acid groups do not usually have any effect on the biological activity but will increase the rate of

elimination of an analogue.


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128 Thiols, Sulphides and Other Sulphur Groups



usually introduced into leads in SAR studies because they are readily metabolised by oxidation.
thiols are some times introduced into a lead structure when improved metal chelation is the objective of the SAR study.
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and sulphide groups are not



For example, the antihypertensive captopril was developed from the weakly active carboxyacylprolines by

replacement of their terminal carboxylic acid group (which is only a

weak ligand for forming complexes with metals) by a thiol group.


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The introduction of thiourea and thioamide groups is usually avoided because these groups may produce goitre, which is a swelling on the neck due to enlargement of the thyroid gland.


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2.3.3 Changing the Existing Substituents of a Lead


can also be formed by replacing an existing substituent in the structure of a lead by a new


substituent group. of isosteres.

choice of group will depend on the objectives of the design team. It is often made using the concept
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some similarities in their chemical and/or physical properties.

a result, they can exhibit similar pharmacokinetic and pharmacodynamic properties.

are groups that exhibit



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In other words, the replacement of a

lead than the totally random selection of an alternative substituent. However, luck still plays a part and an isosteric analogue may have a totally different type of activity from its lead.
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substituent by its isostere is more likely to result in the formation of an analogue with the same type of activity as the


Table 2.3. Examples of bioisosteres. Each horizontal row represents a group of structures that are isosteric.


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identical outer shells of electrons

Classical isosteres were originally defined by This definition has now been broadened to include groups that produce compounds that can sometimes have similar biological activities (Table 2.3). These groups are frequently referred to as bioisosteres in order to distinguish them from classical isosteres.
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Erlenmeyer as being atoms, ions and molecules that had identical outer shells of electrons.



A large number of drugs have been discovered by isosteric and bioisosteric interchanges. For example, the replacement of the 6hydroxy group of hypoxanthine by a thiol group gave the antitumour drug 6mercaptopurine whereas the replacement of hydrogen in the 5position of uracil by fluorine resulted in fluorouracil which is also an antitumour agent.

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However, not all isosteric changes yield compounds with the same type of activity: the replacement of the: -S- of the neuroleptic phenothiazine drugs by either CHCH- or CH2CH2produces the dibenzazepines, which exhibit antidepressant activity (Figure 2.9).


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2.9. Examples of drugs discovered by isosteric replacement.

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sahabat, dakilah terjalnya bukit yg hrs kau daki, turunilah dalamnya lembah yg hrs kau turuni, sebrangilah derasnya arus yg harus kau sebrangi, pikullah beratnya beban yg hrs kupikul, tahanlah perihnya sakit yg harus kau rasa, telanlah pilunya sedih yg hrs kau reguk, dan sahabat semua ini untukmu..., untuk qita.... (aza)
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sahabat, kan q daki terjalnya bukit yg hrs q daki, q turuni dalamnya lembah yg hrs kuturuni, q sebrangi derasnya arus yg harus q sebrangi, q pikul beratnya beban yg hrs kupikul, q tahan perihnya sakit yg harus q rasa, q telan pilunya sedih yg hrs q reguk, dan sahabtq semua ini untukmu..., untuk qita.... (aza)
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