Download Structure- Activity Relationships (SAR)

Structure- Activity Relationships (SAR)
The field of medicinal chemistry has evolved from an
emphasis on the synthesis, isolation, and characterization of
drugs to an increased awareness of the biochemistry of
disease states and the design of drugs for the prevention of
diseases. An important aspect of medicinal chemistry has
been to establish a relationship between chemical
structure and biological activity.
An increased consideration in recent years has been to
correlate the chemical structure with chemical reactivity or
physical properties and these correlations can, in turn, be
related to their therapeutic properties.
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Structure- Activity Relationships (SAR)
• Although there has been a great deal of success in
understanding the relationship between chemical structure
and biological activity in a number of areas, especially for
antibacterial drugs, there are still many human afflictions that
require new and improved drugs. Cancer, viral infections,
cardiovascular diseases, and mental diseases need new
agents and approaches for treating and preventing these
illnesses.
• 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 difference in potency and unwanted side effects and in
some cases different activities. These structurally related
differences are commonly referred to as StructureActivity Relationships (SAR)
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Structure- Activity Relationships (SAR)
• A study of the Structure- Activity Relationships (SAR) of
a lead compound (the original pharmacologically
active compound from which these synthetic
analogues are developed is known as lead
compound) and it’s analogues can be used to
determine the parts of the structure of the lead that are
responsible for it’s biological activity, that is, it’s
pharmacophore and also it’s unwanted side effects.
This information is subsequently used to develop a new
drug that has
• increased activity (optimize it’s 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 (SAR)
• 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.
• Over the years numerous lead compounds have been
investigated and from the mass of data it is possible to make
some broad generalizations about biological effects of specific
structural changes. These changes may be conveniently
classified as:
1. the size and shape of the carbon skeleton,
2. the nature and degree of substitution, and
3. the stereochemistry of the lead.
• The selection of the changes required to produce analogues of
a particular lead is made by considering the activities of
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compounds with similar structures and also the possible
chemistry and biochemistry of the intended analogue.
Structure- Activity Relationships (SAR)
• For example, replacing a hydroxyl group with a methyl group could reduce
the water solubility of the analogue and it’s ability to form hydrogen bonding.
• The former could reduce it’s ease of absorption whereas the latter could
affect it’s ability to bind to it’s target site.
• It could improve the transport of the drug through membranes and also
introduce changes in the metabolism of the drug.
• For example, oxidation of the methyl group to a carboxylic group could
increase the rate of metabolism.
• All these effects could result in loss of activity or a reduction in unwanted
side effects.
• 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 it’s intended target
site.
• Computerized molecular modeling can be used to check this provided that
the structure of the target is known or can be simulated with some degree of
accuracy.
• Traditional SAR investigation procedures are useful tools in the search for
new drugs. However, they are expensive in both personnel and materials.
Consequently, a number of attempts have been made to improve on
traditional Structure- Activity investigations with varying degree of success.
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Structure- Activity Relationships (SAR)
• Changing size and shape
The shapes and sizes of molecules can be
modified in a variety of ways, such as:
1.Changing the number of methylene groups in
chains and rings;
2. ↑ or ↓ the degree of unsaturation:
3.Introducing or removing a ring system.
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Structure- Activity Relationships (SAR)
• Changing the Number of Methylene Groups in a Chain
• Increasing the number of methylene groups in a chain or ring increases
the size and the lipid nature (lipophilicity) of the compound.
• The biological response curves associated with this increase in size can
assume a variety of shapes.(Fig.a).
• It is believed that the increase in activity with increase in number of
methylene groups is probably due to an increase in lipid solubility of the
analogue, which gives a better membrane penetration. Conversely, a
decrease in activity (Fig.b) with an increase in number of methylene
groups is attributed to a reduction in water solubility of the analogues.
This reduction in water solubility can result in the poor distribution of the
analogue in the aqueous media as well as the trapping of the analogue
in the biological membranes
• A further problem with large increase in the umber of inserted methylene
groups in a chain structure is micelle formation. Micelle formation
produces large aggregates that, because of their shape, cannot bind to
active sites and receptors.
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Structure- Activity Relationships (SAR)
Changing size and shape
Changing the Number of Methylene Groups in a Chain
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Structure- Activity Relationships (SAR)
Changing size and shape
• Introducing chain branching, different sized rings
and the substitution of chains for rings and vice
versa may also 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
clomipramine.
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Structure- Activity Relationships (SAR)
Changing
size and shape
Changing the Number of Methylene Groups in a Chain
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Structure- Activity Relationships (SAR)
Changing size and shape
Changing the Degree of Unsaturation
1.The removal of double bonds increases the degree of flexibility of the
molecule, which may make it easier for the analogue to fit into active and
receptor sites by making up a more suitable conformation. However , an
increase in flexibility could also result in a change or loss of activity.
2.The introduction of the double bond increases the rigidity of the structure. It
may also introduce the complication of E- and Z-isomers, which could have
quite different activities.
3.The analogues produced by the introduction of unsaturated structures into a
lead compound may exhibit different degree of potency or different type of
activities.
–
For example, the potency of prednisone is about 30 times greater than that of
it’s parent cortisol, which does not have a 1-2 C=C bond.
4.The replacement of S atom of the antipsychotic phenothiazine drugs by a –
CH=CH- group gives the antidepressant dibenzazepine drugs, such as
protriptyline.
5.The introduction of a C=C group will often give analogues that are more
sensitive to metabolic oxidation. This may or may not be desirable feature for
the new drug.
6.Furthermore, the reactivity of C=C frequently causes the analogue to be
more toxic than the lead.
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Structure- Activity Relationships (SAR)
Changing size and shape
Changing the Degree of Unsaturation
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Structure- Activity Relationships (SAR)
Changing size and shape
• 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 target site,
which might strengthen the binding of the drug to the target.
For example, it has been postulated that the increased
inhibitory activity of the cyclopentyl analogue (rolipram) of
3-(3,4-dimethoxyphenyl)-butyrolactam towards cAMP
phosphodiesterase is due to the cyclopentyl group filling a
hydrophobic pocket in the active site of the enzyme.
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of a Ring System
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of a Ring System
• 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 it’s target site. It
also reduces the possibility of complications caused by the
existence of conformers. However, the selection of the
system for a particular analogue may depend on the
objective of the alteration.
• For example, the cyclopropane ring is usually more stable
than the ethylenic C=C and so could be used to replace this
group if a more stable compound of a similar size is
required. For example the antidepressant tranylcypromine is
more stable than it’s analogue1-amino-2-phenylethene.
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of a Ring System
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Structure- Activity Relationships (SAR)
Changing size and shape
• Introduction or Removal of a Ring System
• The insertion of aromatic system into the structure of the lead will
introduce rigidity into the structure as well as increase the size of the
analogue. The latter means that small aromatic systems such as
benzene and five membered heterocyclic systems are preferred to
larger systems. However, the π electrons of aromatic systems may or
may not improve the binding of the analogue to it’s 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. For example, the replacement of
N-dimethyl group of chlorpromazine by an N-methylpiperazine 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 presence of extra tertiaryamine group
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of Ring System
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Structure- Activity Relationships (SAR)
Changing size and shape
• Introduction or Removal of a Ring System
• The incorporation of a ring systems, especially larger
systems into a structure of a lead can be used to produce
analogues that are resistant to enzymatic attack by sterically
hindering the access of the enzyme to the relevant
functional group. For example, the resistance of
diphenicillin to ß-lactamse is believed to be due to the
diphenyl group preventing the enzyme from reaching the ßlactam. It is interesting to note that 2-phenylbenzylpenicillin
is not resistant to ß-lactamase attack. In this case, it appears
that the diphenyl group is too far away from the ß-lactam
ring to hinder the attack of the ß-lactamase.
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of Ring System
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Structure- Activity Relationships (SAR)
Changing size and shape
• Introduction or Removal of a Ring System
• Many of the potent pharmacologically active
naturally occurring compounds, such as the alkaloid
morphine and curare, have such complex structures
that it would not be economical to synthesize them on
large scale. Furthermore, they also tend to exhibit
unwanted side effects. 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.
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Structure- Activity Relationships (SAR)
Changing size and shape
Introduction or Removal of a Ring System
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• The formation of analogue by introduction of new substituents into the
structure of a lead may result in an analogue with significantly different
chemical and hence pharmacokinetic properties. For example, the
introduction of a new substituent may cause significant changes in
lipophilicity that affect transport of the analogue through 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.
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.
• Each substituent will impart it’s own characteristic properties to the
analogue. However, it is possible to generalize about the effect of
introducing a new substituent group into a structure but there will be
numerous exceptions to the predictions.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Methyl Groups.
• The introduction of methyl groups increases the lipophilicity of
the compound and reduces it’s water solubility. It should improve
the ease of absorption of the analogue into a biological
membrane but will make it’s release from biological membranes
into the aqueous media more difficult. P values for Toluene, 490,
Propionamide 360, N-methlurea 44.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Methyl Groups
• 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
antihistaminic activity. Harmes and colleagues suggest that this
could be due to the ortho-methyl restricting rotation about C-O
bond of the side chain. This prevents the molecule from
adopting the conformation necessary for antihistaminic activity. It
is interesting to note that the para-methyl analogue is 3.7 times
more active than diphenhydramine
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Methyl Groups
• The incorporation of a methyl group can have
one of three general effects on the rate of
metabolism of a analogue:
– an ↑ rate of metabolism due to oxidation of methyl
group;
– an ↑ in rate of metabolism due to demethylation
by the transfer of methyl group to another
compound; or
– a ↓ in the rate of metabolism of the analogue. 26
Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Methyl Groups
•
i) A methyl group bound to an aromatic ring or a structure which
increases it’s reactivity may be metabolized to a carboxylic acid, which
can be eliminated more easily. For example , the antidiabetic tolbutamide
is metabolized to it’s less toxic benzoic acid derivative.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
•
Methyl Groups
(ii) Demethylation is more likely to occur when the methyl group
is attached to positively charged nitrogen and sulphur
atoms, although it is possible for any methyl group attached
to nitrogen, oxygen or sulphur atom to act in this manner. A
number of methyl transfers have been associated with
carcinogenic action.
(iii) Methyl groups can reduce the rate of metabolism of a
compound by masking a metabolically active group, thereby
giving the analogue a slower rate of metabolism than the
lead. For example the action of the agricultural fungicide
nabamis due to it being metabolised to the deactive
diisothiocyanate. N-Methylation of nabam yeilds and
analogue that is inactive because it cannot be metabolised
to the diisothiocyanate.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
Methyl Groups
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
Methyl Groups
• Methylation can also reduce the unwanted side affects of
a drug. For example, mono and di ortho-methylation with
respect to the phenolic hydroxy group of paracetamol
produce analogues with reduced hepatotoxity. It is
believed that this reduction is due to the methyl groups
preventing metabolic hydroxylation of these ortho
positions.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Halogen Groups
• The incorporation of halogen atoms into 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
the lipid tissues.
• 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. For aliphatic carbon-halogen bonds C-F bond is the
strongest and usually less chemically reactive than aliphatic CH bonds.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Halogen Groups
• The other aliphatic C-halogen bonds are weaker, their reactivity
increases 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 electron-withdrawing ring substituents may increase their
reactivity to unacceptable level. Trifluorocarbon groups (-CF3)
are sometimes used to replace chlorine because these groups
are of a similar size. These substitutions avoid introducing a
very reactive centre and hence 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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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Halogen Groups
• The changes in potency caused by the introduction of a halogen or
halogen-containing groups will, as with substitution by other
substituents, depends on the position of the substitution. 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 ortho
chlorine groups impose a conformation restriction on the structure of
Clonidine, which probably accounts for its increased activity.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Hydroxy Groups
• The introduction of hydroxy groups into the structure of lead will normally
produce analogues with increased hydrophilic nature and a lower lipid
solubility. It also provides a new centre for hydrogen bonding which could
influence the binding of the analogue to its target site. For example, the
orthohydroxylated minaprine analogue binds more effectively to M1muscarinic receptors than many of its non-hydroxylated analogues. The
introduction of hydroxy group also introduces a centre that, in the case of
phenolic groups, could act as a bacteriocide 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 drugs
from reaching its target.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• 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 lead
will produce analogues that have a lower lipophilicity but an increased water
solubility. 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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Structure- Activity Relationships (SAR)
Introduction of New Substituents
•
Basic Groups
•
The introduction of basic group may increase the binding of an analogue
to its target by hydrogen bonding between that target and the basic group.
(as in Fig.a).
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. (as in Fig.b). For example, it is believed
that many local anaesthetics are transported to their site of action in the
form of their free bases but are converted to their 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 often very toxic and carcinogenic.
•
•
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Carboxylic and Sulphonic Acid Groups
• The introduction of acid groups into the structure of a lead
usually results in analogues with an increased water but
reduced lipid solubility. This increase in water solubility may be
enhanced subsequently by in vivo salt formation. In general the
introduction of carboxylic and sulphonic acid groups into a lead
produces analogues that can be eliminated more readily. The
introduction of carboxylic acid groups into small lead molecules
may produce analogues that have a different type of activity or
are inactive. For example, the introduction of carboxylic acid
group into phenol results in the activity of the compound
changing from being a toxic antiseptic to the less toxic antiinflammatory salicylic acid. Similarly, the incorporation of
carboxylic acid group into the sympathomimetic
phenylethylamine gives phenylalanine which has no
sympathomimetic activity.
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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Carboxylic and Sulphonic Acid Groups
• However, the introduction of carboxylic acid groups
appears to have less effect on the activity of large
molecules. 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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Structure- Activity Relationships (SAR)
Introduction of New Substituents
• Thiols, Sulphides and other Sulphur Groups.
• Thiols and sulphide groups are not usually introduced into leads
in SAR studies because they are readily metabolized by
oxidation.
• However, thiols are sometimes introduced into a lead structure
when improved metal chelation is the objective of the SAR
studies. 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.
• The introduction of thiourea and thiamide groups is usually
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avoided because these groups may produce goiter.
Structure- Activity Relationships (SAR)
Changing the Existing Substituent of a Lead
• Analogues can also be formed by replacing an existing
substituent in the structure of lead by a new substituent
group.The choice of group will depend on the objectives of
design team. It is often made using the concept of Isosteres.
• Isosteres are groups that exhibit some similarities in their
chemical and/or physical properties. As a result, they can
exhibit similar pharmacokinetic and pharmacodynamic
properties. In other words, the replacement of a substituent by
it’s isostere is most likely to result in the formation of an
analogue with the same type of activity as the lead than the
totally random selection of an alternative substituents.
• However, luck still plays a part and an isosteric analogue may
have a totally different type of activity from it’s lead.
• Classical isosteres were originally defined by Erlenmeyer as
being atoms, ions and molecules that had identical outer shells
of electrons. This definition has now been broadened to include
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groups that produce compounds that can sometimes have
Structure- Activity Relationships (SAR)
Changing the Existing Substituent of a Lead
Examples of bioisosteres
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Structure- Activity Relationships (SAR)
Changing the Existing Substituent of a Lead
A large number of drugs have been discovered by isosteric and
bioisosteric interchanges. For example, the replacement of the 6hydroxy group of hypoxanthine by thiol group gave the
antitumour drug 6-mercaptopurine whereas the replacement of
hydrogen in the 5 position of uracil by fluorine resulted in
fluouracil, 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 -CH=CH- or -CH2-CH2- produces the dibenzazepines,
which exhibit antidepressant activity.
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Structure- Activity Relationships (SAR)
Changing the Existing Substituent of a Lead
Examples of drugs discovered by isosteric replacement
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