Transcript Analogues

Optimizing Target Interactions
Stages of drug design and development
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 - optimizing target interactions
8) Drug design - optimizing pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials
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
Structure-activity relationships (SAR)
• 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
Structure-activity relationships (SAR)
HO
MORPHINE
O
NMe
HO
Structure-activity relationships (SAR)
H3CO
CODEINE
O
NMe
HO
ACTIVITY DROPS
Structure-activity relationships (SAR)
HO
MORPHINE
O
NMe
HO
Structure-activity relationships (SAR)
HO
6-OXYMORPHINE
O
NMe
O
ACTIVITY UNAFFECTED
Structure-activity relationships (SAR)
Important groups for activity
HO
MORPHINE
O
NMe
HO
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
R OMe
CH3COCl
R
O
CH3
Ether
Ester
O
CH3SO2Cl
R
O
S
OO
CH3
LiAlH4
R H
Alkane
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
SAR on 1o, 2o & 3o amines (RNH2, RNHR, R3N)
Possible binding interactions if amine is ionized
Drug
NH2R
+
Ionic
CO2Binding site
H-Bonding
Drug
HBD
+
N
R2
+
H
R3NH acts as a
strong HBD
X
X= N or O
Binding site
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
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
Notes
• 1o and 2o amines are converted to 2o and 3o amides respectively
• Amides cannot ionize 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)
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
SAR on quaternary ammonium salts (R4N+)
Possible binding interactions
Drug
Drug
Ionic
bonding
NR3
NR3
+
+
d-
CO2Binding site
Analogues
Full synthesis of 1o-3o amines and amides
Binding site
d+
Induced
dipole
interactions
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
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
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
Carboxylic acid
LiAlH4
R
Alcohol
OH
C
H2
o
1 Alcohol
Notes
• 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 reactive
functional groups are present
SAR on esters
Notes
• 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
Fatty
Barrier
Esterase
O
C
R
O
OH
O
C
Drug
C
R
O
O
Prodrug
O
O
C
O
R
Esterase
Drug
C
O
Ester masks polar groups
Allows passage through
fatty cell membranes
R
OH
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)
Notes
• The nitrogen of an amide cannot act as a HBA - lone pair interacts with
neighboring carbonyl group
• Tertiary amides unable to act as HBD’s
SAR on amides
Analogues
R
C
H
N
R'
NaOH
R
C
OH
+
H2N R'
O
O
Carboxylic acid
LiAlH4
R
C
H2
Amine
NH2
1o Amine
NaH / MeI
CH3
N
C
R'
R
O
o
3 Amide
Notes
• 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 reactive groups
are present
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
SAR on carboxylic acids
Possible binding interactions as free acid
Drug
O
Drug
O
C
HBA
O
C
H
HBA
O
H
H
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)
SAR on carboxylic acids
Possible binding interactions as carboxylate ion
Drug
Drug
O
O
C
HBA
O
C
-
-
Ionic bonding
O
H
X
Binding site (X= N or O)
+
NHR2
Binding site (X= N or O)
Notes
• Charged oxygen atoms are strong HBA’s
• Group can interact by ionic and hydrogen bonding at the same time
SAR on carboxylic acids
R
Possible analogues
C
OH
H+ / R'OH
R
C
OR'
O
O
Ester
LiAlH4
R
C
H2
OH
1o Alcohol
Possible effects
• Reduction removes carbonyl oxygen as potential HBA and prevents ionization
• Esterification prevents ionization, HBD interactions and may hinder HBA by
a steric effect
Analogue
Analogue
O
C
O
O
steric shield CH3
C
O
CH3
+
NHR2
H
X
binding site
No ionic bonding possible
H-Bonding hindered
SAR on aromatic rings and alkenes
Possible effects on binding
Analogue
Analogue
‘Buffers’
R
R
H H
H
No
fit
H
binding site
hydrophobic
pocket
binding site
hydrophobic
region
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 -react with nucleophiles in DNA
• 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
Notes
• 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)
SAR of alkyl groups
Possible interactions
Drug
van der Waals
interactions
Drug
binding site
binding site
H3C CHCH3
3
hydrophobic ‘pocket’
hydrophobic slot
CH3
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
N H
H
HBr
Analogue
O
OR'
Analogue
O
O
R'OH
C
C
R'
Analogue
OH
Hydrolysis
N R'
R'X
O
O
OCH3
Drug
R'X
H
C
O