Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Gareth Thomas
11/7/2013
prof. aza
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.
prof. aza 2
11/7/2013
lead compounds
The
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.
11/7/2013 prof. aza 3
Natural products
Lead compounds
11/7/2013 prof. aza 4
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
11/7/2013
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).
11/7/2013
prof. aza
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.
11/7/2013
prof. aza
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.
11/7/2013
prof. aza
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.
11/7/2013
prof. aza
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.
11/7/2013
prof. aza
10
Compound analog
11/7/2013
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.
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.
prof. aza 13
11/7/2013
11/7/2013
15
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.
prof. aza 16
11/7/2013
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.
prof. aza
11/7/2013
17
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.
11/7/2013
prof. aza
19
Once the structure of the proposed lead has been decided it becomes the responsibility of the medicinal chemist to devise a synthetic
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.
prof. aza 20
11/7/2013
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.
11/7/2013
prof. aza
21
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.
11/7/2013
prof. aza
22
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
11/7/2013
23
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.
11/7/2013
prof. aza
24
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.
Other
11/7/2013
prof. aza
26
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
11/7/2013
27
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.
11/7/2013 prof. aza
unsaturated groups of all types and saturated ring systems (Figure 2.2). The
28
Esters/Amide
Aliphatic conjugatisc systems
Aromatic sytems
Heteroaromatic systems
29
11/7/2013
prof. aza
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
potency
11/7/2013
prof. aza
30
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.
11/7/2013 prof. aza 31
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.
For
Archer
activity.
due to the anti or staggered conformation whereas the nicotinic activity was due to the syn or eclipsed form (Figure 2.3).
11/7/2013 prof. aza 33
Figure 2.3. Syn and anti conformers of acetylcholine and 2-tropanyl ethanoate methiodides.
11/7/2013 prof. aza 34
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
11/7/2013
prof. aza
35
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.
11/7/2013 prof. aza
36
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
prof. aza 37
11/7/2013
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.
11/7/2013 prof. aza 38
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).
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.
11/7/2013
prof. aza
40
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.
prof. aza
11/7/2013
41
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.
2.2.3 Configuration
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).
11/7/2013
prof. aza
44
The consequence of these differences is that it is now necessary to make and test separately all the individual stereoisomers of a drug.
prof. aza 46
11/7/2013
As well as an effect on the activity, different stereoisorners will also change other physiochemical properties such as absorption,
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.
prof. aza 47
11/7/2013
11/7/2013
prof. aza
48
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
prof. aza
49
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
effects.
11/7/2013 prof. aza
50
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.
11/7/2013
prof. aza
51
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.
prof. aza 52
11/7/2013
Over the years numerous lead compounds have been investigated and from the mass of data it is possible to make some broad generalisations about
11/7/2013
prof. aza
53
the size and shape of the carbon skeleton. (2) the nature and degree of substitution, and (3) the stereochemistry of the lead.
11/7/2013 prof. aza 54
The
and also the possible chemistry and biochemistry of the intended analogue.
11/7/2013 prof. aza 55
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.
prof. aza 56
11/7/2013
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.
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.
11/7/2013
prof. aza
58
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 .
11/7/2013
prof. aza
59
system.
11/7/2013
prof. aza
60
of the compound. The biological response curves associated with this increase in size can assume a variety of shapes (Figure 2.6a).
11/7/2013 prof. aza 61
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.
prof. aza 62
11/7/2013
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
11/7/2013
prof. aza
64
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.
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.
11/7/2013 prof. aza 66
Introducing chain branching, different sized rings and the substitution of chains for rings and vice versa may also
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.
11/7/2013 prof. aza 67
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
68
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.
11/7/2013 prof. aza 69
is about 30 times greater than that of its parent compound cortisol, which
11/7/2013
prof. aza
70
The introduction of a C=C group will often give analogues that are more
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
lead.
11/7/2013
prof. aza
71
2.3.1.3 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
11/7/2013
72
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.
prof. aza 73
11/7/2013
11/7/2013
prof. aza
74
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.
prof. aza 75
11/7/2013
For example,
the
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.
11/7/2013 prof. aza 76
cyclopropane ring is usually more stable than the ethylenic C=C group and so could be used to
11/7/2013
prof. aza
77
The
insertion of aromatic systems into the structure of the lead will introduce rigidity into the structure as well as increase the
aromatic systems
The
78
However, the electrons of aromatic systems may or may not improve the
which could also affect the potency and activity of the analogue.
11/7/2013 prof. aza 79
For example,
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.
prof. aza 80
11/7/2013
11/7/2013
prof. aza
81
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
the
11/7/2013 prof. aza
11/7/2013
prof. aza
83
The
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.
11/7/2013 prof. aza
84
For example,
the resistance of diphenicillin to -lactamase
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.
11/7/2013 prof. aza
85
Many
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.
prof. aza 86
11/7/2013
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).
prof. aza
11/7/2013
87
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).
11/7/2013
prof. aza
88
11/7/2013
prof. aza
89
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.
11/7/2013 prof. aza 90
formation of analogues by the introduction of new substituents into the structure of a lead may result in an
91
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.
11/7/2013 prof. aza 92
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.
prof. aza
11/7/2013
93
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.
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.
11/7/2013 prof. aza 96
11/7/2013
prof. aza
97
The
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.
11/7/2013
prof. aza
98
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.
11/7/2013 prof. aza 99
restricting rotation about the C-O bond of the side chain. This prevents the
11/7/2013
prof. aza
100
(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.
11/7/2013 prof. aza 102
11/7/2013
prof. aza
103
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
11/7/2013
104
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
11/7/2013
11/7/2013
prof. aza
106
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
hepatotoxicity.
It is believed that this reduction is due to the methyl groups preventing metabolic hydroxylation of these ortho positions.
11/7/2013 prof. aza 107
11/7/2013
prof. aza
108
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
110
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,
11/7/2013
prof. aza
111
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.
Consequently,
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.
11/7/2013 prof. aza 113
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.
prof. aza 114
11/7/2013
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.
prof. aza 115
11/7/2013
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.
prof. aza
11/7/2013
116
11/7/2013
prof. aza
117
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
11/7/2013
For example, the ortho-hydroxylated minaprine analogue binds more effectively to M1-muscarinic receptors than many of its non-hydroxylated analogues.
11/7/2013
prof. aza
119
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.
11/7/2013
prof. aza
120
analogue, the more likely it will form salts and the less likely it will be transported through a lipid membrane.
11/7/2013
prof. aza
122
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
11/7/2013
123
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
11/7/2013
124
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
2.3.2.5 Carboxylic and Sulphonic Acid Groups The introduction of carboxylic acid groups into small lead molecules may produce analogues that have a very
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
126
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.
prof. aza 127
11/7/2013
Sulphonic acid groups do not usually have any effect on the biological activity but will increase the rate of
elimination of an analogue.
11/7/2013
prof. aza
128
However,
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.
prof. aza
11/7/2013
129
For example, the antihypertensive captopril was developed from the weakly active carboxyacylprolines by
11/7/2013
prof. aza
130
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.
11/7/2013
prof. aza
131
can also be formed by replacing an existing substituent in the structure of a lead by a new
The
choice of group will depend on the objectives of the design team. It is often made using the concept
prof. aza 132
11/7/2013
Isosteres
As
11/7/2013
prof. aza
133
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.
11/7/2013 prof. aza
substituent by its isostere is more likely to result in the formation of an analogue with the same type of activity as the
134
Table 2.3. Examples of bioisosteres. Each horizontal row represents a group of structures that are isosteric.
11/7/2013
prof. aza
135
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.
prof. aza
Erlenmeyer as being atoms, ions and molecules that had identical outer shells of electrons.
11/7/2013
136
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.
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).
11/7/2013
prof. aza
138
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)
prof. aza 140
11/7/2013
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)
prof. aza 141
11/7/2013
11/7/2013
prof. aza
142
11/7/2013
prof. aza
143