Drug Modification Lead Discovery

• To improve the activity and properties of the

• Random.
lead compound.
• Nonrandom.
• Drug metabolism studies.
• Clinical observations.
• Rational approaches.

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Drug Modification Drug Modification Strategies

• Variation of substituents.
• To improve the activity and properties of the
• Extension of the structure.
lead compound.
• Alkyl chain extensions/contractions.
• Ring expansions/contractions.
Binding interactions activity.
• Ring variations
• Ring fusions.
Selectivity side-effects.
• Isosteres & Bioisosteres.
• Simplification of the structure.
Alteration of water/lipid solubility (ADME).
• Rigidification of the structure.
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 Drug Modification Strategies Alteration in Alkyl Chains
• Variation of substituents.
• Extension of the structure. • Chain length (±CH2), Branching, and Changing
• Alkyl chain extensions/contractions. ring size:
• Ring expansions/contractions.
• Ring variations
Lipophilicity/Hydrophilicity (ADME).
• Ring fusions.
• Isosteres & Bioisosteres.
Drug-Receptor Interaction.
• Simplification of the structure.
• Rigidification of the structure.
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Branching: Branching:

• Promethazine is an antihistamine.
• Promazine is an antipsychotic.
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Branching: Branching:

Drug Drug

CH3 H3C C CH3

CH3
hydrophobic
pocket

poor interaction good interaction

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Chain length:

R R
N N
R CH3 Fit No Fit R CH3
steric
block
N CH3 Fit Fit N CH3
• or alkyl chain Selectivity Toxicity.

Receptor 1 Receptor 2

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• Chain length is critical for ideal Drug-Receptor
Interaction.
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• Agonistic versus antagonistic action.
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• Development of angiotensin converting • Development of angiotensin converting

enzyme (ACE) inhibitors. enzyme (ACE) inhibitors.
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 hydrophobic
pocket

CH3 CH3
O N O N
N N
H COO H COO
O O O O

binding site

CH3
O N
N
H COO
O O

• Development of angiotensin converting • Development of angiotensin converting

enzyme (ACE) inhibitors. enzyme (ACE) inhibitors.
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Simplification of the Structure

hydrophobic
pocket

CH3 CH3
O N O N
N N
O
H
O COO O
H
O COO
• Reduction of complex molecules to simpler
binding site
structures with retention of the desired
biological action.
CH3 CH3
O N O N
N N
O
H
O COO O
H
O COO • The pharmacophore constitutes a small
portion of the molecule.
• Development of angiotensin converting
enzyme (ACE) inhibitors (thousand-fold).
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• Tetracyclic compound with five chiral centers.

Respiratory depression.

Addiction.

High cost of synthesis.
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Isosterism

• Lead compound.
• The undesirable properties.
• Replacement or modification of functional

Pharmacokinietic.
groups with other groups having similar

Pharmacodynamic. properties is known as isosteric replacement,
• Specific functional groups. or bioisosteric replacement.
• Modification.

Isosteric replacement.

Bioisosteric replacement.
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 Property N2O CO2
• Chemical isosterism (Langmuir,1919).
• Similarities in physical properties among Viscosity at 20°C 148 x 10-6 148 x 10-6
atoms: Density of liquid at 10°C 0.856 0.858

Same number of valence electrons. Refractive index of liquid, D line 16°C 1.193 1.190

Same columns within the periodic table.
Dielectric constant of liquid at 0°C 1.593 1.582
• It works for some functional groups, radicals,
and small molecules. Solubility in alcohol at 15°C 3.250 3.130

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Grimm’s Hydride Displacement Law Limitations

C N O F • Physicochemical properties are not always

similar.
CH NH OH • For example: CH3, OH and NH2.
CH2 NH2
H-bonding (OH and NH2).

Basicity (NH2).
CH3

Lipophilicity (CH3).
• Pseudoatoms: • Actual location, motion, and resonance of

Same number of valence electrons. electrons within orbitals (not considered).

Different number of atoms.
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 Ring Equivalents

• Hinsberg applied the concept of isosterism to

entire molecules.
• Ring equivalents:
groups that can be exchanged for one another
in aromatic ring systems without drastic
changes in physicochemical properties relative
to the parent structure.

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Bioisosterism
• Was introduced by Friedman.
• Functional groups or molecules that have
chemical and physical similarities producing
broadly similar biological properties (e.g.
insulin).
• Bioisosteric replacement in drug modification
is highly dependent on the biological system
being investigated.
• Example: H1-receptor antagonists.
• Bioisosteric replacement / Particular receptor.
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 • Functional groups that satisfy the original
conditions of Langmuir and Grimm are
• Bioisosteric groups:
referred to as classical bioisosteres.

Classical bioisosteres.
• Nonclassical bioisosteres do not obey steric
and electronic definitions of classical

Nonclassical bioisosteres. bioisosteres and do not necessarily have the
same number of atoms as the substituent
they replace.

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Classical Bioisosters

• Monovalent.
• Divalent.
• Trivalent.
• Tetravalent.
• Ring equivalents.

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 • Electronic properties.
• Hydrophobicity.
• Electronegativity. • Size.
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Nonclassical Bioisosteres

• Nonclassical bioisosteres are replacements of

functional groups not defined by classical
definitions.
• Some of these groups, however, mimic spatial
arrangements, electronic properties, or some
other physicochemical properties of the
molecule or functional group critical for
biological activity. Ring versus Noncyclic!

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 Exchangeable groups!

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O NH O N
Cl N Cl N
N NH2 N NH2
H
H2N N NH2 H2N N NH2

OH OH

H H

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 O NH O N O NH O N
Cl N Cl N Cl N Cl N
N NH2 N NH2 N NH2 N NH2
H H
H2N N NH2 H2N N NH2 H2N N NH2 H2N N NH2

OH OH R OH OH R
O N O N
N N
OCH3 O OCH3 O
S S
N N N N
H H CH3 CH3 H H CH3 CH3

H2 H2 NH2 NH2
S COOH C COOH S COOH C COOH
N N N N
NH2 NH2 NH2 NH2
N N N N
HO HO H2
O C

OH OH

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