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STRUCTURE ACTIVITYRELATIONSHIPS (SAR’s)
(Chapter No. 7)
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• Once the structure of lead compound is known, the
medicinal chemist moves on to study its SAR.
• The aim is to discover which parts of the molecule areimportant to biological activity and which are not.
• SAR is synthesizing compounds, where one particularfunctional group of the molecule is removed or altered.
• In this way it is possible to find out which groups are
essential and which are not for biological effect.
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INTRODUCTION TO STRUCTURE
ACTIVITY RELATIONSHIP
There are various aims in establish SAR’s
1.The drug should have a good selectivity for its target
2.The drug should have a good level of activity for its target
3.The drug should have minimum side effects
4.The drug should be easily synthesized
5.The drug should be chemically stable
6.The drug should have acceptable pharmacokinetics properties
7.The drug should be non-toxic
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There are two important aspects in drugdesign and drug strategies to improve :
1. Pharmacodynamics properties: to optimize the interaction of
the drug with its target.
2. Pharmacokinetics properties: to improve the drug's ability to
reach its target & to have acceptable life time.
Pharmacodynamics and pharmacokinetics should have equal
priority in influencing which strategies are used and which
analogues are synthesized
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Determine pharmacodynamics and pharmacokinetics of the drug.
Pharmacodynamics explores what a drug does to the body, whereas
pharmacokinetics explores what the body does to the drug (The study of
absorption, distribution, metabolism and excretion of a drug (ADME) is
called Pharmacokinetics)
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• This involves testing all analogues for biological activity andcomparing them with the original compound.
• If an analogue shows a significant lower activity, then thegroup that has been modified must be important.
• If the activity remain similar, then the group is not
essential.
• It may be possible to modify some lead compounds directlyto the required analogues and other analogues may be
prepared by total synthesis.
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Binding Role of Different FunctionalGroups
• 1-Functional groups such as alcohols, phenols, amines,esters, amides, carboxylic acids, ketones and aldehydescan interact with binding sites by means of hydrogenbonding.
• 2- Functional groups such as amines, (ionized)quaternary ammonium salts and carboxylic acid caninteract with binding sites by ionic bond.
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Ar (R) O
H
....
HBD
HBA
HBA Alcohol or Phenol
Ar (R) O
O
Ar (R) O..
.. HBA
Ester
....
HBA..
..
Methyl ether
Analogues
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Amines
Ionized amines and quaternaryammonium salts
NRR
R
NHR
R
NHH
R
..
HBA
3OAmine
..
HBA
2oAmine
HBD
..
HBA
1oAmine
HBDHBD
N+
RR
R
R
O O
Binding SiteIonic bond
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• 3- Functional groups such as alkenes and aromatic rings can interactwith binding sites by means of Van der Waals interactions.
R Aromatic ring
Good interaction Flat hydrophobic binding region
R Cyclohexane
Poor interaction Flat hydrophobic binding region
R
RR
R
Flat hydrophobic binding region
Alkene
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• 4- Alkyl substituents and the carbon skeleton of the leadcompound can interact with hydrophobic regions of binding siteby means of Van der Waals interactions.
•
5-Interactions involving dipole moments or induced dipolemoments may play a role in binding a lead compound to a bindingsite.
• 6-Reactive functional groups such as alkyl halides may lead toirreversible covalent bonds being formed between a lead
compound and its target.• E.g. alkylation of macromolecular target by alkyl halides
X R NH2 Target R N
H
Target XAlkyl halide
+
..
Nucleophilic group
Alkylation
+ Good leaving
group
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• The relevance of a functional group to binding can be determinedby preparing analogues where the functional group is modified or removed in order to see whether activity is affected by such
change.
• Some functional groups can be important to the activity of a leadcompound for reasons other than target binding as they may play arole in the electronic or stereochemical properties of the compoundor they may have an important pharmacokinetic role.
• In vitro testing procedures should be used to determine the SAR fortarget binding.
•The pharmcophore summarizes the important groups which areimportant in the binding of a lead compound to its target, as wellas their relative positions in three dimensions (for a specificpharmacological activity).
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Drug Optimization:Strategies in drug designI-Optimizing drug target inetractions
»Drug optimization aims to maximize the interactions of a drug with its targetbinding site in order to improve activity, selectivity and to minimize sideeffects.
»Designing a drug that can be synthesized efficiently and cheaply is anotherpriority.
»The aim of drug optimization can be achieved by differentstrategies or approaches on the lead compound SAR, such as;
»1-variation of substituents (alkyl and aromatic substitution)
»2- extension of structure (chain extension/contraction, ringexpansion/contraction),
»3-ring variation,»4-ring fusion,
»6-simplification of the structure,
»7- Rigidification of the structure.
»8-Conformational blockers
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Drug Optimization:Strategies in drug design
I-optimizing drug target inetractions • 1-The length and size of alkyl substituents can be
modified to fill up on hydrophobic pockets in the bindingsite or to introduce selectivity for one target over another.
Alkyl groups attached to heteroatoms are most easilymodified.
• Aromatic substituents can be varied in character and/or ringposition.
• 2-Extension is a strategy where extra functional groups areadded to the lead compound in order to interact with extrabinding region in binding site.
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• Chains connecting two important binding groups can be
modified in length in order to maximize the interactions of
each group with the corresponding binding regions.
• Rings linking important binding groups can be expanded or
contracted such that the binding groups bind efficiently withrelevant binding regions.
• Rings can be fused to existing rings in order to maximize
binding interactions or to increase selectivity for one target
over another.
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»Classical and non-classical isosteres (bioisisteres)
»are frequently used in drug optimization.
»Simplification involves removing functional groups from the lead
compound that are not part of the pharmacophore. Unnecessaryparts of the carbon skeleton or asymmetric centers can also beremoved in order to design drugs that are easier and cheaper tosynthesize. Oversimplification can result in molecules that are tooflexible, resulting in decreased activity and selectivity.
Some examples of isosteres include:
Sodium and hydrogen cations
Carbon dioxide (CO2) and nitrous oxide
(N2O)
Silicon and carbon
methyl, amide, and hydroxyl groups
such as benzene and
thiophene, thiopheneand furan, and even
benzene and pyridine,
exhibited similarities in
many physical and
chemical properties
Biosteres
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• Conformational blockers are groups which are introduced into
a lead compound to reduce the number of conformations that
the molecule can adopt through steric interactions.
• Structure- based drug design makes use of X-ray
crystallography and computer-based molecular modeling to
study how a lead compound and its analogues bind to a targetbinding site.
• Molecular Modeling
• Also important parameter for determination of molecule bind
with ligand with stable conformation and which part of molecule will actively involved in biological system.
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• Oxamniquine (schistosomicides) is an example of a drug designed byclassical methods.
NH
OH
N
H
O2N
Oxamniquine
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Drug Design:II-Optimizing access to the target
•The compound with the best binding interaction is notnecessarily the best drug to use in medicine.
• The drug needs to pass through many barriers to reach itstarget in the body.
•
There are many ways to make the drug to reach its target suchas linking the drug to polymers or antibodies or encapsulatingit within a polymeric carrier.
• Thus, the aim is to design drugs that will be absorbed into theblood supply (absorption) and will reach their target efficiently(distribution) and be stable enough to survive the journey(metabolism) and will be eliminated in a reasonable period of time (elimination).
• In other words, designing a drug with optimum
pharmacokinetics can be achieved by different strategies.
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Improvement of absorption:
• Drug absorption is determined by itshydrophilic/hydrophobic.
• Drugs which are too polar or strongly ionized do not easily
cross the cell membranes of the gut wall. Therefore, they aregiven by injection, but the disadvantage that they are quicklyexcreted.
• Non-polar drugs, on the other hand, are poorly soluble in
aqueous solution and are poorly absorbed. If they are givenby injection, they are taken up by fat tissue.
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Strategies to improve absorption
• 1)- Variation of alkyl or acyl substituents to vary polarity:
• A- Molecules can be made less polar by masking a polarfunctional group with an alkyl or acyl group.
• For example: an alcohol or phenols can be converted to esteror amide. Primary and secondary amines can be converted to
amides or secondary or tertiary amines.
• B-Polarity is decreased not only by masking the polar groups,but by addition of an extra hydrophobic alkyl group (large alkylgroups having a greater hydrophobic effect).
• Extra alkyl groups can be added to carbon skeleton directly ormay involve more synthesis.
• If the molecule is not sufficiently polar then the oppositestrategy can be used i.e. replacing large alkyl groups withsmaller alkyl groups or removing them entirely.
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Strategies to improve absorption
• 2)- Varying polar functional groups to vary polarity
• A polar functional group could be added to a drug to increasepolarity.
• For example: Ticonazole (antifungal) is used only for skininfections because it is non-polar and poorly absorbed in bloodby introducing a polar hydroxyl group and more polar
heterocyclic ring led to the orally active antifungal agentFluconazole.
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• In contrast, the polarity of an excessively polar drug could belowered by removing polar functional groups.
• It is important not to remove functional groups which areimportant to the drug's binding interactions with itstarget.
S
NN
Cl
OH
Cl
Cl
NN
N
N
N
N
F
OOH
FIncrease Polarity
Ticonazole Fluconazole
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Strategies to improve absorption
3)- Variation of N-alkyl substituents to vary pka• Drugs with a pka outside the range 6-9 tend to be too strongly
ionized and are poorly absorbed through cell membrane.
• In general, electron donating groups (EDG, e.g. alkyl groups)
increase basicity (increase pka). But increasing the size of alkyl
groups will increase the steric bulk around the nitrogen (Steric
hindrance) leading to a decrease of basicity of amine.
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• For example: Benzamidine (antithrombotic), the amidine group(H2NC=NH) is too basic for effective absorption. Incorporating this
group into an isoquinoline ring system reduced basicity andincreased absorption (see structure).
N
N
N
NH2
NH
N
O
H O
N
N
N
N
O
H O
N NH2
Amidine
BenzamidinePRO3112
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Strategies to improveabsorption•4)- Variation of aromatic substituents• The aromatic amine or carboxylic acid can be varied by adding
EDG or electron withdrawing groups or substituents (EWG) to
the ring.
• The position of the substituent is important too if the
substituent interacts with the ring through resonance.
• In general, EWG increase acidity and EDG decrease acidity.
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I-Making drugs more resistant tochemical and enzymaticdegradation
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»There are various strategies that can be used to makedrug more resistant to hydrolysis and drug
metabolism and thus prolonged their activity (moreduration of action) such as:
»1)- Steric shields
»Some functional groups are more susceptible tochemical and enzymatic degradation than other.
» For example: esters and amides are prone tohydrolysis. A common strategy that is used toprotect these groups is to add steric shields.
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•Steric shields, designed to hinder the approach of anucleophile or an enzyme to the susceptible group.These usually involve the addition of a bulky alkyl
group close to the functional group. For example: t-butyl group in the antirheumatic agent (D1927)serves as a steric shield and blocks hydrolysis of terminal peptide bond.
N OO
SHN
O
H O
NH
CONHMe
D1927
Steric shields have also been used to
protect penicillins from lactams and toprevent drug interacting with
cytochrome P450 enzymes.
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•2) Metabolic Blockers• Some drugs are metabolized by introducing of polar functional
groups at particular positions in their skeleton.
• For example: Megestrol acetate (oral contraceptive) is oxidized atposition 6 to give OH group at this position. Bu introducing a methylgroup at position 6, metabolism is blocked and the activity of thedrug is prolonged.
O
O
O
O
Megestrol acetate
17α-acetoxy-6-dehydro-6-methylprogesterone,
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3)- Removal of susceptible metabolic groups
Certain chemical groups are particularlysusceptible to metabolic enzymes. e.g. methylgroups on aromatic rings are often oxidized to
carboxylic acids which then quickly eliminatedfrom the body.
Other common metabolic reactions include
aliphatic and aromatic C-hydroxylation, N- & S-oxidations, O & S-dealkylations and deamination.
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• 5)- Ring Variation
•Certain ring systems are often found to besusceptible to metabolism and so varying thering can often improve metabolic stability.
•e.g. replacement of imidazole ring (susceptible to
metabolism) in Tioconazole with 1,2,4-triazole ringgives Fluconazole with improved stability as shownpreviously.
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S
NN
Cl
OH
Cl
Cl
NN
N
N
N
N
F
OOH
FIncrease Polarity
Ticonazole Fluconazole
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Making drug less resistance to drug
metabolism•Drug that is extremely stable to metabolism andis very slowly excreted can cause problems as
that is susceptible to metabolism. Such as causetoxicity and side effects.
•Therefore, designing drugs with decreasedchemical and metabolic stability can sometimes
be useful.
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•1)- Introducing metabolically susceptible groups
• Introducing groups that are susceptible tometabolism is a good way of shorting the lifetimeof a drug.
•For example: methyl group was introduced tosome drug to shorten its lifetime because methylcan metabolically oxidized to polar alcohol as well
as to a carboxylic acid.