Lead optimization

Rana H. Refaey
Lecture ILOs

By the end of this lecture students should be able to:

• Discuss the different methods of lead optimization
• Apply the proper method for lead optimization
• Differentiate between classical and non-classical isosteres
• Predict classical and non classical isosteres
Lead Optimization

• The aim of lead optimization is to find analogs of

the lead compound which have better properties
(higher activity, higher selectivity, lower
incidence of side effects)
• There are two important areas in which the lead
compound needs to be optimized;
• The interactions between the drug and the target.
• The ability of the drug to reach the its biological
target.
Lead Optimization

• There are several main strategies for lead

optimization
• Molecular manipulation
• Hybridization
• Simplification
• Rigidification
• Bioisosteres
• Prodrugs and soft drugs
Molecular manipulation

1. Changing the size and shape

2. Simplification of the structure
3. Rigidification of the structure
4. Obstructive groups and steric shielding
1. Changing the size and
shape of the molecule

This includes a variety of modifications that can be

applied such as;
1. The changing of the number of carbons in chains
or rings
2. The introduction or removal of ring systems
3. Addition of new substituents
1. Changing the size and
shape of the molecule

• The variation of alkyl substituents allows the

exploration of the binding pocket and choosing
the substituent which fills the pocket increasing
binding interactions
Example
1. Changing the size and
shape of the molecule

• The increase in the size of alkyl group may

increase the selectivity of the compound
Example
H OH H OH
HO NH HO NH CH3
CH3
CH3
HO HO
Isoprenaline
Epinephrine
 agonist only
  agonist
1. Changing the size and
shape of the molecule

Example

β-receptor has
an
α-
extra
receptor
hydrophobic
pocket
1. Changing the size and
shape of the molecule

• The introduction of a ring may result in an

increase in the number of interactions, improving
the binding with the pocket
Example
H3CO
H3CO O
O O
H3CO NH
NH
Rolipram
Antidepressant 10X more potent
1. Changing the size and
shape of the molecule

• The introduction of a ring may result in an

increase in the number of interactions, improving
the binding with the pocket
Example CH3 CH3
N N

OH

HO O O HO O OH
Oxymorphine Phenethylmorphine
2.5 times more active than morphine 14 times more active than morphine
1. Changing the size and
shape of the molecule
• The changing of the size of a ring changes the
relative position of the substituents or other rings
which may lead to better interactions
Example
1. Changing the size and
shape of the molecule
• The introduction of a ring may decrease the rate
of metabolism (less liable for metabolism)
Example H3C CH
CH COOH
3
NSOH2C CH2CH2N 2
CH3
H3C METABOLISM
NH
NH in vivo
Indole acetic acid
(inactive metabolite)
Antimigraine drug
Short acting

CH3
N

Resist metabolism
NH Long acting drug

Locked side chain

in Pipridine
1. Changing the size and
shape of the molecule
• Rings already present in the structure maybe
opened to facilitate synthesis
Example
OH OH

HO
HO
Diethylstilbesterol
Estradiol
Contraceptive
Contraceptive
Less expensive
1. Changing the size and
shape of the molecule
• A new substituent maybe added to the molecule
to interact with an unused region in the binding
pocket
Example
1. Changing the size and
shape of the molecule
• The addition of a hydrophobic group may occupy
a previously unoccupied pocket increasing the
potency of the compound
Example
1. Changing the size and
shape of the molecule
• May be employed to change an agonist into an
antagonist (How?)
Example
CH3
N N

HO O O HO O OH
morphine nalorphine
µ agonist µ antagonist
1. Changing the size and
shape of the molecule
• The choice of the substituent can be used to
change the physicochemical properties of the
molecule
Example
Group Properties Effect
• Increased lipophilicity • Better absorption
Methyl group
• Decreased solubility • Faster metabolism
• Hydrogen bond ?
• decreased lipophilicity
Hydroxy group • increase in rate of
• Increased solubility
elimination
1. Changing the size and
shape of the molecule
Example
Group Properties Effect
• decreased lipophilicity • Hydrogen bond ?
Amino group • Increased solubility (salt • aromatic amine are
formation) avoided (toxic)
• decreased lipophilicity
Carboxylic & • Increase in rate of
• Increased solubility (salt
sulphonic elimination
formation)
2. Hybridization

• involves combining two or more structurally

distinct lead compounds to create a hybrid
molecule.
• This approach aims to take advantage of the
favorable characteristics of each compound.
• hybrid molecules can exhibit improved potency,
selectivity, or other desired properties.
2. Hybridization
3. Structure simplification

• This strategy is normally applied to natural

compounds with complex structures
• After the identification of essential groups, the
remaining non-essential parts are discarded
• Structure simplification is advantageous due to
1. Facilitate the synthesis process
2. Decrease production cost
3. Production of more selective compounds
4. Decrease the incidence of side effects
3. Structure simplification

Example H3C
N
Et
N
O Et O

O O

Cocaine Procaine
Local anaesthetic properties Local anaesthetic
O O
H3C CH3
NH O O N
H3C N N CH3
CH3 CH3 NH
H3C

Physostigmine Neostigmine
Muscarininc with side effects Muscarininc with less side effects
4. Structure rigidification

• It involves the locking of the structure into its

active conformation, this increases the activity
and decreases side effects.
• This can be done by incorporating the flexible
bond into a cyclic structure
Example
4. Structure rigidification

• Structure rigidification can also be done by the

incorporation of rigid functional groups, e.g.
multiple bonds, amides or aromatic rings.
Example
Isosteres

• Classical isosteres: are atoms or a group of atoms

that have the same number of electrons in the outer
shell and thus have similar physical and/or chemical
properties, but don’t necessarily have the same
biological properties.
• Nonclassical isosteres: are atoms or a group of
atoms that don’t follow the same rules as classical
isosteres, but can retain biological activity by
mimicking certain properties of the functional group
Bioisosteres

• Bioisosteres: are atoms or groups which can be

interchanged while retaining the same biological
activity.
• These are normally used to replace functional
groups important for target binding but in other
ways problematic.
• They include classical isosteres and non classical
isosteres.
Classical isosteres

• Periodic table isosteres: Atoms of the same

column in the periodic table
Classical isosteres

• Pseudoisosteres: according to Grimm’s hydride

displacement law. Atoms of the same row of the
periodic table + (1 to 4) hydrogens
Classical isosteres

C N O F
Si P S Cl
CH NH OH
CH2 SH
NH2
CH3
Classical isosteres

• Examples: OH SH

N N N N

N N N N
Sugar Sugar

O CH3 O CH3
H3C C O CH2CH2 N CH3 H2N C O CH2CH2 N CH3
CH3 CH3
Acetylcholine Carbacholine
Muscarininc, Short acting Muscarininc, Long acting
Classical isosteres

• Examples: H3C O H3C O

NH NH
O S
Et NH Et NH
O O

Pentobarbital Thiopental
Long acting sedative Ultrashort acting sedative

CONH2 N CONH2

N N
Nicotinamide Pyrazinamide
Poor anti T.B. Potent anti T.B.
Nonclassical isosteres

• Not all physicochemical properties are shared

between nonclassical isosteres
• Thus, their interchangeability depends on whether
the different characteristics are important for
activity
Nonclassical isosteres

Hydroxy group isosteres

1. Hydroxymethyl group (CH2OH)
2. Urea (NHCONH2)
3. Methylsulphonamide (NHSO2CH3)
Amide (CONH) isosteres
4. Reversed amide (CONH)
5. Ester (CO2)
6. Urea (NHCONH)
7. Sulphonamide (NHSO2)
Nonclassical isosteres

Carboxylate isosteres
1. Sulphonamide (SO2NH2)
HN N
2. Tetrazole N
N

3. Sulphonate and phosphate (SO3H & PO3H2)

Nonclassical isosteres

Halogens (F & Cl)

1. Cyano (CN)
2. Trifluoromethyl (CF3)
3. Fluoro atoms can be replaced by hydrogens
Nitro group (NO2)
4. Cyano (CN)
5. Nitro phenyl may be replaced by pyridine

O2N N
Bioisosteres

• Properties affected by isosteric replacement

1. Size
2. Solubility
3. Hydrophobicity
4. H- bond formation
5. Stability
H-Halide replacement

• Hydrogen and fluorine have the same size but

fluorine is highly electronegative; useful for
increasing electronegativity without affecting size
• Can be used to increase metabolic stability of easily
oxidized aromatics; H  F (or Cl if size is not critical)
and CH3  CF3
OH-NH2-SH replacement

• All three have the ability to act as H-bond donors

and acceptors.
• O and NH have similar sizes but SH is larger
• O and NH replacements on heterocyclic rings affect
the stability of tautomers
N O N OH
H
More stable

N NH2
N NH
H More stable
COOH replacement

• Phosphate and sulphonate have higher acidities

than carboxylic acid  are ionized at physiological
pH
• Sulphonamide group is less acidic than carboxylic
acid group
• Tetrazole has similar acidity to carboxylic acid but is
more lipophilic
Halogen replacement

• Cyano and CF3 have the same electronic effect but

the cyano group is more hydrophilic
Examples
COOH
COOH
COOH
O N
C3H7 NH
CH3
O
N

O NH2
HC CH2

Cl

O-
N
O
Reference
• Patrick, G.L.,. An introduction to medicinal chemistry. Oxford university
press.
• Williams, D. A. & Lemke, T. L. Foye’s Principles of Medicinal Chemistry
(7th edition), Lippincott Williams & Wilkins ISBN:1609133455
• Edward H. Kerns and Li Di; Drug-like properties: Concepts, Structure,
Designs and Methods , 1st edition, chapters 4-8.
Faculty of
Pharmacy