Transcript No Slide Title

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET
INTERACTIONS
Part 1: Section 10.1 (SAR)
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Contents
Part 1: Section 10.1 (SAR)
1.
2.
Introduction to drug design & development
Structure Activity Relationships (SAR) (2 slides)
2.1. SAR on Alcohols (2 slides)
2.2. SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides)
2.3. SAR on Quaternary Ammonium Salts (R4N+)
2.4. SAR on Aldehydes and Ketones (2 slides)
2.5. SAR on Esters (2 slides)
2.6. SAR on Amides (3 slides)
2.7. SAR on Carboxylic Acids (3 slides)
2.8. SAR on Aromatic Rings and Alkenes (2 slides)
2.9. Miscellaneous Functional Groups in Drugs
2.10. SAR of Alkyl Groups (2 slides)
[26 slides]
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1. Introduction to drug design & development
Stages
1) Identify target disease
2) Identify drug target
3) Establish testing procedures
4) Find a lead compound
5) Structure Activity Relationships (SAR)
6) Identify a pharmacophore
7) Drug design- optimising target interactions
8) Drug design - optimising pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials
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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. Structure Activity Relationships (SAR)
NOTES ON ANALOGUES
•
Modifications may disrupt binding by electronic / steric effects
•
Easiest analogues to make are those made from lead compound
•
Possible modifications may depend on other groups present
•
Some analogues may have to be made by a full synthesis
(e.g. replacing an aromatic ring with a cyclohexane ring)
•
Allows identification of important groups involved in binding
•
Allows identification of the pharmacophore
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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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2.1 SAR on Alcohols
Possible effect of analogues on binding
(e.g. ether)
Ether analogue
Ether analogue
O
steric shield
O
CH3
CH3
H
X
X
X= N or O
Binding site
Binding site
No interaction as HBD
No interaction as HBA
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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Possible binding interactions if amine is ionised
Drug
NH2R
+
Ionic
CO2Binding site
H-Bonding
Drug
HBD
+
N
R2
+
H
X
X= N or O
Binding site
R3NH acts as a
strong HBD
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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Possible binding interactions for free base
H-Bonding
Drug
Drug
HBD
N
R
HBA
H
N
H
X
X= N or O
Binding site
R
H
X
Binding site
Note:
3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD
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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Analogues of
1o & 2o amines
H
N
CH3COCl
R
NH2
CH3
R
O
Effect on binding
O
Amide
analogue
N
R
CH3
CO2Binding site
No interaction
•
•
•
•
1o and 2o amines are converted to 2o and 3o amides respectively
Amides cannot ionise and so ionic bonding is not possible
An amide N is a poor HBA and so this eliminates HBA interactions
Steric effect of acyl group is likely to hinder NH acting as a HBD (2o amide)
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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Analogues of 3o amines containing a methyl substituent
CH3
Demethylation
R NHR
O
O
CH3
VOC-Cl
CH3COCl
R
N
R NHR
R
2o amine
O
3o amide
CH3
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2.3 SAR on Quaternary Ammonium Salts (R4N+)
Possible binding interactions
Drug
Drug
Ionic
bonding
NR3
NR3
+
+
d-
d+
Induced
dipole
interactions
CO2Binding site
Binding site
Analogues
Full synthesis of 1o-3o amines and amides
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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
Possible binding interactions
H-bonding as HBA by either oxygen
Analogues
R
O
C
CH3
NaOH
R
OH
+
C
HO
CH3
O
O
C arboxyl i c aci d
LiAlH4
R
Al coh ol
OH
C
H2
1o Al coh ol
•
•
•
Hydrolysis splits molecule and may lead to a loss of activity due to loss of
other functional groups - only suitable for simple esters.
Hydrolysis leads to a dramatic increase in polarity which may influence
ability of analogue to reach target if in vivo tests are used
Reduction to alcohol removes carbonyl group and can establish
importance of the carbonyl oxygen, but reaction can be difficult to do if
other labile functional groups are present
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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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2.6 SAR on Amides
Possible binding interactions
O
Drug
HBA
H
•
•
HBD
N
R
H
X
X
Binding site (X= N or O)
Binding site (X= N or O)
The nitrogen of an amide cannot act as a HBA - lone pair
interacts with neighbouring carbonyl group
Tertiary amides unable to act as HBD’s
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2.6 SAR on Amides
Analogues
R
C
H
N
R'
NaOH
R
C
OH
+
H2N R'
O
O
C arboxyl i c acid
LiAlH4
R
C
H2
Am i ne
NH2
1o Am i ne
NaH / MeI
CH3
N
C
R'
R
O
o
3 Am i de
•
•
•
Hydrolysis splits molecule and may lead to loss of activity due to loss of
other functional groups - only suitable for simple amides.
Hydrolysis leads to dramatic increase in polarity which may affect ability
of analogue to reach target if in vivo tests are done
Reduction to amine removes carbonyl group and can establish importance
of the carbonyl oxygen, but reaction may be difficult to do if other labile
groups are present
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2.6 SAR on Amides
Analogues
•
N-Methylation prevents HBD interaction and may introduce a steric
effect that prevents an HBA interaction
Analogue
Analogue
O
O
R
N
N
R
steric shield CH3
H
CH3
X
X
binding site
No binding as HBD
Binding of O as HBA hindered
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2.7 SAR on Carboxylic Acids
Possible binding interactions as free acid
Drug
O
Drug
O
C
HBA
O
C
H
H
H
HBA
O
H
X
X
Binding site (X= N or O)
Binding site (X= N or O)
Drug
O
C
O
HBD
H
X
Binding site (X= N or O)
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2.7 SAR on Carboxylic Acids
Possible binding interactions as carboxylate ion
Drug
Drug
O
O
C
HBA
O
C
-
O
H
X
Binding site (X= N or O)
•
•
-
Ionic bonding
+
NHR2
Binding site (X= N or O)
Charged oxygen atoms are strong HBA’s
Group could interact both as an ion and as a HBA at the same
time
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2.7 SAR on Carboxylic Acids
R
Possible analogues
C
OH
H+ / R'OH
R
Este r
LiAlH4
R
C
H2
OH
1o Al coh ol
Possible effects
•
OR'
O
O
•
C
Reduction removes carbonyl oxygen as potential HBA and prevents
ionisation
Esterification prevents ionisation, HBD interactions and may hinder HBA
Analogue
by a steric effect
Analogue
O
C
O
O
steric shield CH3
C
O
CH3
+
NHR2
H
X
binding site
No ionic bonding possible
H-Bonding hindered
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2.8 SAR on Aromatic Rings and Alkenes
Possible binding interactions
Drug
Drug
R
vdw
binding site
R
vdw
binding site
hydrophobic
region
hydrophobic
pocket
Possible analogues
Drug
Drug
H2 / RaNi
R
H
H
R'
H2 / Pd/C
R
H
H
H
R'
H
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2.8 SAR on Aromatic Rings and Alkenes
Possible effects on binding
Analogue
Analogue
‘Buffers’
R
R
H H
H
No
fit
H
hydrophobic
pocket
binding site
binding site
hydrophobic
region
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2.9 Miscellaneous Functional Groups in Drugs
•
•
•
•
•
•
•
•
•
•
Acid chlorides
- too reactive to be of use
Acid anhydrides- too reactive to be of use
Alkyl halides
-present in anticancer drugs to form covalent bonds
with
nucleophiles in target
Aryl halides
-commonly present. Not usually involved in binding
directly
Nitro groups
-sometimes present but often toxic
Alkynes
-sometimes present, but not usually important in binding
interactions
Thiols
-present in some drugs as important binding group to
transition metals (e.g. Zn in zinc metalloproteinases)
Nitriles
- present in some drugs but rarely involved in binding
Functional groups may be important for electronic reasons
(e.g. nitro, cyano, aryl halides)
Functional groups may be important for steric reasons
(e.g. alkynes)
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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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