Transcript No Slide Title

2. Structure Activity Relationships (SAR)
AIM - Identify which functional groups are important for binding
and/or activity
METHOD
• Alter, remove or mask a functional group
• Test the analogue for activity
• Conclusions depend on the method of testing
in vitro - tests for binding interactions with target
in vivo - tests for target binding interactions and/or pharmacokinetics
•
•
If in vitro activity drops, it implies group is important for
binding
If in vivo activity unaffected, it implies group is not important
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2.1 SAR on Alcohols
Possible binding interactions
Drug
Drug
HBD
O
HBA
H
O
X
H
X
H
X= N or O
Binding site
Binding site
Possible analogues
CH3I
R OH
CH3COCl
R
R OMe
Ether
O
Ester
CH3
O
CH3SO2Cl
R
O
S
OO
CH3
LiAlH4
R H
Alkane
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2.4 SAR on Aldehydes and Ketones
Possible binding interactions
Dipole-dipole
interaction
Drug
Drug
HBA
O
O
H-Bonding
H
X
Binding site (X= N or O)
Binding site
Analogues
NaBH4 or LiAlH4
O
R
R'
Ketone
Planar sp2
carbon centre
HO
R
H
R'
2o Alcohol
Tetrahedral sp3
carbon centre
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2.4 SAR on Aldehydes and Ketones
Effect on binding
Change in stereochemistry (planar to tetrahedral)
May move oxygen out of range
Alcohol
analogue
H
OH
H
X
Binding site (X= N or O)
If still active, further reactions can be carried out on
alcohol to establish importance of oxygen
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2.5 SAR on Esters
•
•
Esters are usually hydrolysed by esterases in the blood
Esters are more likely to be important for
pharmacokinetic reasons i.e. acting as prodrugs
Prodrug
Drug
Fatty
barrier
esterase
O
C
R
O
C
C
R
O
O
Prodrug
Drug
O
O
C
O
OH
O
esterase
C
R
O
Ester masking polar groups
allowing passage through
fatty cell membranes
R
OH
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2.10 SAR of Alkyl Groups
Possible interactions
Drug
van der Waals
interactions
Drug
binding site
binding site
H3C CHCH3
3
hydrophobic ‘pocket’
CH3
hydrophobic slot
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2.10 SAR of Alkyl Groups
Analogues
•
•
Easiest alkyl groups to vary are substituents on heteroatoms
Vary length and bulk of alkyl group to test space available
VOC-Cl
Drug
N CH3
CH3
Drug
Drug
R'X
N H
H
HBr
Analogue
OCH3
Analogue
OH
Hydrolysis
O
OR'
Analogue
O
O
R'OH
C
C
R'
R'X
O
O
N R'
H
C
O
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3. PHARMACOPHORE
•
Defines the important groups involved in binding
•
Defines the relative positions of the binding groups
•
Need to know Active Conformation
•
Important to Drug Design
•
Important to Drug Discovery
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HO
MORPHINE
O
NMe
HO
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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY
HO
MORPHINE
O
NMe
HO
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IMPORTANT GROUPS FOR ANALGESIC ACTIVITY
HO
MORPHINE
O
NMe
HO
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ANALGESIC PHARMACOPHORE FOR OPIATES
HO
N
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HO
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
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HO
HO
O
NMe
H3C
NMe
CH3
METAZOCINE
HO
MORPHINE
HO
NMe
LEVORPHANOL
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HO
O
NMe
HO
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O
Ar
N
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O
2.798 A
18.5o
Ar
150o
7.098 A
4.534 A
11.3o
N
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4. DRUG DESIGN
- OPTIMISING BINDING INTERACTIONS
AIM - To optimise binding interactions with target
REASONS
• To increase activity and reduce dose levels
• To increase selectivity and reduce side effects
STRATEGIES
•
•
•
•
•
•
•
•
•
Vary alkyl substituents
Vary aryl substituents
Extension
Chain extensions / contractions
Ring expansions / contractions
Ring variation
Isosteres
Simplification
Rigidification
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4.1 Vary Alkyl Substituents
Adrenaline
H
HO
OH
H
N
CH3
HO
Salbutamol
(Ventolin)
H
HOCH2
OH
H
N
CH3
CH3
(Anti-asthmatic)
HO
Propranolol
(b-Blocker)
C
CH3
CH3
H
O
N
H
CH3
OH
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a-Adrenoceptor
H-Bonding
region
H-Bonding
region
Van der Waals
bonding region
Ionic
bonding
region
H-Bonding
region
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a-Adrenoceptor
ADRENALINE
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a-Adrenoceptor
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b-Adrenoceptor
ADRENALINE
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b-Adrenoceptor
SALBUTAMOL
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b-Adrenoceptor
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
SALBUTAMOL
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a-Adrenoceptor
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4.1 Vary Alkyl Substituents
Notes on synthetic feasibility of analogues
•
Feasible to remove alkyl substituents on heteroatoms
and replace with other alkyl substituents
•
Difficult to modify alkyl substituents on the carbon skeleton of
a lead compound. Full synthesis is usually required
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4.1 Vary Alkyl Substituents
R'
Methods
Drug
O
HBr
H
Drug
O
a) NaH
b) R"I
R"
Drug
O
Ether
Drug
Amine
Me
N
R
OR
Drug
C
VOC-Cl
H
Drug
N
R"
Drug
HO-
OH
Drug
C
O
R
H+
R"OH
OR"
Drug
C
O
O
O
C R
Drug
N
R
O
Ester
R"I
O
HO-
Drug
OH
R"COCl
C R"
Drug
O
Ester
O
Drug
O
C R
NH
H+
NR2
H+
Drug
NH2
R"COCl
Drug
C R"
NH
Amide
Drug
Amide
C
O
OH
Drug
C
O
HNR"2
NR2"
Drug
C
O
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4.3 Extension - Extra Functional Groups
Example : ACE Inhibitors
Hydrophobic pocket
Hydrophobic pocket
Vacant
CH3
CH3
EXTENSION
N
O
O
N
H
Binding
site
O
O
(I)
CO2
N
N
H
Binding
site
O
O
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CO2
4.5 Ring Expansion / Contraction
Vary n
to 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
O 2C
N
N
H
N
H
CO2
O
Ph
Binding regions
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CO2
4.7 Isosteres and Bio-isosteres
Useful for SAR
Me
O
NH
Me
H
OH
Propranolol (b-blocker)
•
•
•
Replacing OCH2 with CH=CH, SCH2, CH2CH2
eliminates activity
Replacing OCH2 with NHCH2 retains activity
Implies O involved in binding (HBA)
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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 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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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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4.9 Rigidification
Rationale :
• Endogenous lead compounds often simple and flexible
(e.g.
adrenaline)
•
Fit several targets due to different active conformations
(e.g. adrenergic receptor types and subtypes)
single bond
rotation
+
+
Flexible
chain
•
Different conformations
Rigidify molecule to limit conformations - conformational
restraint
• Increases activity (more chance of desired active conformation)
• Increases selectivity (less chance of undesired active
conformations)
Disadvantage:
• Molecule more complex and may be more difficult
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to synthesise
4.9 Rigidification
H
NH2Me
H
O
O
NH2Me
H
H
BO ND
RO TATIO N
II
I
O 2C
H
H
NH2Me
O
O
O H
NH2Me
H
RECEPTOR 1
O 2C
O H
H
RECEPTOR 2
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4.9 Rigidification
Methods - Introduce rings
Bonds within ring systems are locked and cannot rotate freely
X
NHMe
Introducing
rings
H
N
X
NHMe
Me
N
X
CH3
X
X
X
NHMe
NMe
Test rigid structures to see which ones have retained active
conformation
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4.9 Rigidification
Examples - Combretastatin (anticancer agent)
Rotatable
bond
OCH3
OH
Z-isomer
H3CO
H3CO
H3CO
OH
E-isomer
H3CO
OCH3
OH
OCH3
Combretastatin A-4
More active
Less active
H3CO
H3CO
OCH3
OCH3
OH
OCH3
Combretastatin
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4.9 Rigidification
Steric Blockers - Examples
H
N
O
H
N
N
CF3
N
Serotonin
antagonist
OMe
Introduce
methyl group
CH3
Steric
clash
H
N
O
N
H
N
N
CH3
H
N
CF3
N
OMe
O
H
N
orthogonal
rings
CF3
N
OMe
Increase in activity
Active conformation retained
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