METHODS OF LEAD OPTIMIZATION
BY
Dr. K.G.LALITHA
PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
JAZAN UNIVERSITY, JAZAN,KSA
Subject: Drug Discovery and Development
Lecture notes – 3 rd year, 6 th semester, Pharm.D
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PHARMACODYNAMIC OPTIMIZATION
⚫ It is to optimize the binding interactions of the
lead with the target
⚫ It is carried out by SAR studies and
PHARMACOPHORE IDENTIFICATION
STRUCTRURE ACTIVITY RELATIONSHIP (SAR)
⚫ It involves the identification of regions or
functional groups important for binding of the
drug to target
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⚫ Practically SAR studies can be carried out
using X-ray crystallography and Molecular
Modeling software
⚫ Traditionally SAR is carried out by
synthesizing analogues of the lead where
one particular functional 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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BINDING ROLE OF DIFFERENT FUNCTIONAL GROUPS AND
THEIR ANALOGUES
⚫ Functional groups such as alcohols, phenols,
amines, esters, amides, carboxylic acids, ketones
and aldehydes can interact with binding sites by
means of hydrogen bonding
Analogues prepared to test binding interactions
are:
⚫ Phenols and alcohols - esters and ether derivatives
⚫ Ketones are reduced to alcohol derivatives
⚫ Aldehydes may be oxidized to carboxylic acid
derivatives
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⚫ Amines could be converted to their corresponding
amides by treating with acyl chlorides
⚫ Amides could be converted to amines, ketones, alkenes
and acids to test the binding interactions
⚫ Esters may be converted to ether
⚫ Carboxylic acid may be converted to ester, ketone,
primary alcohol and primary amide
⚫ Functional groups such as amines, (ionized) quaternary
ammonium salts and carboxylic acid can interact with
binding sites by ionic bond
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Possible hydrogen bonding interactions for
alcohol or phenol
Binding interactions for different amines
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Interactions of ionized amines
Interaction of quaternary ammonium compound
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Functional groups such as alkenes and aromatic rings can
interact with binding sites by means of Van der Waals
interactions
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• Alkyl substituent and the carbon skeleton of the lead
compound can interact with hydrophobic regions of binding
site by means of Van der Waals interactions.
• Interactions involving dipole moments or induced dipole
moments may play a role in binding a lead compound to a
binding site.
• Reactive functional groups such as alkyl halides may lead to
irreversible covalent bonds being formed between a lead
compound and its target.
E.g. alkylation of macromolecular target by alkyl halides
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PHARMACOKINETIC OPTIMIZATION
⚫ Involves the optimization of pharmacokinetic properties
of the lead
⚫ The compound with the best binding interaction is not
necessarily the best drug to use in medicine.
⚫ The drug needs to pass through many barriers to reach
its target in the body
⚫ Thus, the aim is to design drugs that will be absorbed
into the blood 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)
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ABSORPTION OF DRUGS
⚫ Drug absorption is determined by its
hydrophilic/hydrophobic properties, which
depends upon polarity and ionization.
⚫ Drugs which are too polar or strongly ionized do
not easily cross the cell membranes of the gut
wall. Therefore, they are given by injection, but
the disadvantage that they are quickly excreted.
⚫ Non-polar drugs, on the other hand, are poorly
soluble in aqueous solution and are poorly
absorbed. If they are given by injection, they are
taken up by fat tissue.
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STRATEGIES TO IMPROVE ABSORPTION
1.Variation of alkyl or acyl substituent to vary polarity:
⚫ Molecules can be made less polar by masking a
polar functional group with an alkyl or acyl group.
⚫ An alcohol or phenol can be converted to ester or
amide. Primary and secondary amines can be
converted to amides or secondary or tertiary
amines.
⚫ Polarity is decreased by addition of an extra
hydrophobic alkyl group (large alkyl groups having
a greater hydrophobic effect)
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2. Varying polar functional groups to vary polarity:
• A polar functional group could be added to a drug to
increase polarity.
• Ticonazole (antifungal) is used only for skin infections
because it is non-polar and is poorly absorbed in blood.
• Introduction of a polar hydroxyl group and more
polar heterocyclic ring led to the orally active
antifungal agent Fluconazole
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3.Variation of N-alkyl substituent 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
⚫ The pKa of an amine can be altered by varying the alkyl
substituents
⚫ 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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Benzamidine (antithrombotic), the amidine group
(H2NC=NH) is too basic for effective absorption.
Incorporating this group into an isoquinoline ring
system reduced basicity and increased absorption
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METABOLISM OF DRUGS
I-Making drugs more resistant to chemical and
enzymatic degradation:
1 Steric shields
⚫ Some functional groups are more susceptible to
chemical and enzymatic degradation than other.
⚫ Esters and amides are prone to hydrolysis. A
common strategy that is used to protect these
groups is to add steric shields.
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Steric shields are designed to hinder the approach of
a nucleophile 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.
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2. Metabolic Blockers
• Some drugs are metabolized by introducing a polar functional
group at particular positions in their skeleton.
• Megestrol acetate (oral contraceptive) is oxidized at position 6 to
give OH group at this position .But introducing a methyl group
at position 6, metabolism is blocked and the activity of the drug
is prolonged
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3. Removal of susceptible metabolic groups
⚫ Certain chemical groups are particularly susceptible
to metabolic enzymes. E.g. methyl groups on
aromatic rings are often oxidized to carboxylic acids
which then quickly eliminated from the body
⚫ The methyl group of Tolbutamide (anti diabetic)
was replaced by a chlorine atom to give
chlorpropamide which is much longer lasting
4. Ring Variation
⚫ Replacement of imidazole ring (susceptible to
metabolism) in Ticonazole with 1,2,4-triazole ring
gives Fluconazole with improved stability.
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II. Making drug less resistance to drug metabolism
⚫ Drug that is extremely stable to metabolism is very
slowly excreted and can cause problems such as
toxicity and side effects.
Introducing metabolically susceptible groups:
⚫ Methyl group was introduced to some drugs to
shorten its lifetime because methyl can metabolically
oxidized to polar alcohol as well as to a carboxylic
acid.
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TARGETING DRUGS
⚫ Targeting drugs to particular tissue or cell would
result in safer drugs with reduced side effects
⚫ Drugs can be linked to amino acids or nucleic acid
bases to target them against fast-growing and rapidly
dividing cells in the treatment of cancer, as
aminoacids or nucleic acids are needed in large
amounts by the dividing cells
⚫ Drugs can be targeted to the GIT by making them
ionized or highly polar such that they can not cross
the gut wall. Example: Pthalyl sulfathiazole
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REDUCING TOXICITY
⚫ It is often found that a drug fails clinical trials because
of its toxic side effects.
⚫ It is known that functional groups such as aromatic
nitro groups, aromatic amines, bromoarenes, hydrazines,
hydroxylamines, or polyhalogenated groups are often
metabolized to toxic products. Varying or eliminating
these substituent would reduce toxicity.
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REFERENCES
Graham L.Patrick, An Introduction to
Medicinal Chemistry, Fourth Edition, Oxford
University Press, New York, 2009, 212 - 252
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