Transcript No Slide Title

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET
INTERACTIONS
Part 4: Section 10.3.8
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Contents
Part 4: Section 10.3.8
4.8. Simplification
Rationale
Methods (9 slides)
Example (2 slides)
Disadvantages (14 slides)
Example of oversimplification (8 slides)
[36 slides]
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4.8 Simplification
Rationale :
•
•
•
•
Lead compounds from natural sources are often complex and
difficult to synthesise
Simplifying the molecule makes synthesis of analogues easier,
quicker and cheaper
Simpler structures may fit binding site easier and increase
activity
Simpler structures may be more selective and less toxic if
excess functional groups removed
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4.8 Simplification
Methods:
•
•
Retain pharmacophore
Remove unnecessary functional groups
OH
HOOC
Ph
Cl
Drug
NHMe
OH
Ph
Drug
NHMe
OMe
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4.8 Simplification
Methods:
•
Remove excess rings
Example
HO
HO
HO
O
N
CH3
N
H
H
H
H
CH3
N
Me
Me
H
H
HO
Morphine
Excess functional groups
Lev orphanol
Metazocine
Excess ring
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CH3
4.8 Simplification
Methods:
•
Remove asymmetric centres
H
X
X
C
N
Y
Chiral
drug
Asymmetric centre
H
X
Y
Achiral
drug
C
C
Y
Chiral
drug
Y
X
Asymmetric centre
Y
Achiral
drug
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4.8 Simplification
Methods:
•
Simplify in stages to avoid oversimplification
CH3
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H3C
N
GLIPINE
N
CH3
A
N
CH3
B
N
CH3
CH3
H
C
N
CH3
D
Pharmacophore
•
•
Simplification does not mean ‘pruning groups’ off the lead
compound
Compounds usually made by total synthesis
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4.8 Simplification
Example
Me
N
Et2NCH2CH2
CO2Me
O
H
C
O
O
C O C AINE H
O
C
PRO C AINE
NH2
Pharmacophore
•
•
•
Important binding groups retained
Unnecessary ester removed
Complex ring system removed
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4.8 Simplification
Example
Benzodiazepine
O
Me
N
N
N
OH
NH
O
H
HN
Indole
O
H
N
N
H
O
N
H
N
O
Asperlicin - CCK antagonist
Possible lead for treating panic attacks
Devazepide
Excess rings removed
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4.8 Simplification
Disadvantages:
•
•
•
Oversimplification may result in decreased activity and
selectivity
Simpler molecules have more conformations
More likely to interact with more than one target binding site.
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Target binding site
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Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Target binding site
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Rotatable bonds
Different binding site - side effects
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4.8 Simplification
Example of oversimplification
•
Simplification of opiates
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MORPHINE
O
C
C
C
C
C
C
N
SIMPLIFICATION
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LEVORPHANOL
O
C
C
C
C
C
C
N
SIMPLIFICATION
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LEVORPHANOL
O
C
C
C
C
C
C
N
SIMPLIFICATION
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METAZOCINE
O
C
C
C
C
C
C
N
SIMPLIFICATION
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O
C
C
C
C
C
C
N
OVERSIMPLIFICATION
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TYRAMINE
O
C
C
C
C
C
C
N
OVERSIMPLIFICATION
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AMPHETAMINE
O
C
C
C
C
C
C
N
OVERSIMPLIFICATION
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