Drug Discovery &
Development
Lec 3
II. Special approach
1. Variation of alkyl substituents.
2. Extention of the structure.
3. Ring closure or ring opening
4. Ring expansion and ring contraction
5. Homologation and chain branching
6. Introduction of unsaturation center
7. Introduction, removal or replacement of bulky
groups
8. Changes of substitution position
9. Introduction of chiral center
10. Conformation restriction (molecular rigidification)
11. Isosteres and bioisosteres
1. Variation of alkyl substituents.
The length and size of alkyl substituents can be
modified to fill up on hydrophobic pockets in the
binding site or to introduce selectivity for one
target over another. Alkyl groups attached to
heteroatoms are most easily modified.
Rationale:
• Alkyl group in lead compound may interact with hydrophobic
region in binding site
• Vary length and bulk of group to optimise interaction
ANALOGUE
LEAD COMPOUND
CH3
H3C
C
CH3
CH3
Hydrophobic
pocket
van der Waals
interactions
Rationale:
Vary length and bulk of alkyl group to introduce
selectivity
No Fit
N
CH3
N
CH3
Fit
N
CH3
Fit
Fit
Receptor 1
N
CH3
Receptor 2
Binding region for N
Steric
Block
Example:
HO
H
OH
HO
H
N
CH3
HOCH2
H
OH
H
N
CH3
CH3
HO
Adrenaline
C
CH3
Salbutamol
(Anti-asthmatic)
2. Extension of structure
DRUG
RECEPTOR
Unused
binding
region
DRUG
Drug
Extension
RECEPTOR
Extra
functional
group
Example: ACE Inhibitors
Hydrophobic pocket
Hydrophobic pocket
Vacant
CH3
CH3
EXTENSION
N
O
O
N
H
Binding
site
O
O
(I)
N
N
H
CO2
Binding
site
O
O
CO2
Extension - extra functional groups
Example: Nerve gases and medicines
O(CHMe2)
F
P
CH3
O
Sarin
(nerve gas)
OEt
H3C
H3C
S
N
P
CH3
O
OEt
Ecothiopate
(medicine)
Notes:
• Extension
- addition of quaternary nitrogen
H3C
• Extra ionic bonding interaction
H3C
• Increased selectivity for cholinergic receptor
• Mimics quaternary nitrogen of acetylcholine
O
CH3
N
CH3
O
Acetylcholine
Extension - extra functional groups
Example: Second-generation anti-impotence drugs
O
CH3
CH3
O
CH3
N
HN
H
N
HN
N
N
N
O
S
O
N
CH3
N
N
N
O
S
N
Viagra
CH3
Notes:
• Extension - addition of pyridine ring
• Extra van der Waals interactions and HBA
• Increased target selectivity
N
CH3
O
CH3
3. Ring closure or ring opening
Diethylstilbesterol may be regarded as a ``ring opening``
modification of estradiol
Closure of a chain or opening of a ring
Ring chain transformation
4-Ring expansion and ring contraction
Ring
expansion
R
R
R
R
Hydrophobic regions
Ring expansion / contraction
vary
ring
size
Example:
Binding site
O2C
Ph
(CH2)n
N
N
H
O
CO2
N
N
O2C
Ph
Binding site
N
I
O
N
O2C
N
N
H
N
H
CO2
O
CO2
Ph
Binding regions
Two interactions
Carboxylate ion out of range
Three interactions
Increased binding
5- Homologation
A homologous series is a group of compounds that
differ by a constant unit, generally a CH2 group
This phenomenon corresponds to Increased lipophilicity of the
molecule to permit penetration into cell membranes until its
lowered water solubility becomes problematic in its transport
through aqueous media.
e.g. 1: Hypnotic activity of alcohols
The maximum effect occurred for 1-hexanol to 1-octanol.
The potency declined on chain lengthening until no activity
was observed for hexadecanol.
e.g. 2: 4-alkyl substituted resorcinol derivatives
[Antibacterial effect is maximum in case of 4-n-hexyl resorcinol]
Chain branching
Chain branching lowers the potency of a compound because a
branched alkyl chain is less lipophilic than the corresponding
straight alkyl chain.
in case of [Homologation]
lipophilic relationship is important
The lowered potency may be due to
pharmacokinetics
(Absorption, metabolism, excreation,……..etc)
pharmakodynamics
Chain branching may interfere with receptor binding
The primary pharmacologic activity of promethazine is that
of an antihistamine, whereas promazine is an antipsychotic.
The only difference between the two molecules is the
alkylamine side chain. In the case of promethazine, there is
an isopropylamine side chain, whereas promazine contains
an n-propylamine.
S
S
N
N
N
N
Promethazine
Promazine
6. Introduction of unsaturation center
The double bond in prednisolone increases its antirheumatic
activity over its parent compound, cortisol by about 30 fold
O
HO
O
O
OH
HO
OH
O
Cortisol
Prednisolone
OH
OH
Thank you & have a
nice vacation