MacKerell, Lead Modification 1
Lead Modification (or Lead Optimization)
Objectives: Once a lead compound has been identified it must be systematically altered to
obtain the desired properties (maximize the therapeutic index and minimize side
effects). Alternatively, a known agonist or substrate can be structurally modified to
make an antagonist or an inhibitor by maintaining the structural characteristics associated
with binding and specificity but not "activation" of the biological activity (e.g. the HIV
protease inhibitors where the lead compound was the substrate). At the end of this lecture
the student will know the concepts of therapeutic index and of the pharmacophore, based
on the opioids, and the traditional methods used for optimization of lead compounds to
improve their biological activity.
Oral contraceptives are an example
biochemical pathway: regulation of menstration and pregnancy
steriods (e.g. progesterone) identified as mediating compounds; therefore
used as lead compounds
modification of physiological steroids leads to active agents
(contraceptives)
Figure 1) Structures of progesterone and (+)-norgestrel
Therapeutic index (therapeutic ratio)
measure of the ratio of undesirable to desirable drug effects (multiple
bioassays)
in vivo: LD50/EC50 = therapeutic index
LD50: the lethal dose for 50 % of the test animals
EC50: the effective dose that produces the maximum therapeutic effect in
50% of the test animals
, MacKerell, Lead Modification 2
the larger the therapeutic index the greater the safety of the drug: goal of
lead optimization
Pharmacophore (similar to SAR with sulfa drugs)
Functional group types (e.g. hydrogen bond donors, acceptors, hydrophobic regions) and
the spatial arrangement of those groups on a molecule that interact with the receptor and
are responsible for binding and biological activity.
Ideally separate the binding pharmacophore from the activity pharmacophore to design a
compound that binds but does not cause the biological activity (antagonist). For
example, with the opioids, determine the individual pharmacophores for the analgesic
and addictive properties.
First identify the pharmacophore and then design compounds that systematically deviate
from the pharmacophore to obtain desired efficacy.
Pharmacophore identification via functional group modification
1) systematically alter or remove portions of the molecule
2) identify regions essential for activity (or different types of activities)
3) note that pharmacological data is sometimes ambiguous (i.e. data is not
clear cut yes or no, but often somewhere in between), requiring care when
interpreting relationships of structure to activity.
Opioids as an example (morphine)
Note that physiological substrates for opioid receptors were not known for many
years (endorphins, enkephalins, dynorphins and others).
Figure 2) Structure of morphine, codeine and heroin
1) Remove tetrahydrofuran ring and hydroxyl at R'
Lead Modification (or Lead Optimization)
Objectives: Once a lead compound has been identified it must be systematically altered to
obtain the desired properties (maximize the therapeutic index and minimize side
effects). Alternatively, a known agonist or substrate can be structurally modified to
make an antagonist or an inhibitor by maintaining the structural characteristics associated
with binding and specificity but not "activation" of the biological activity (e.g. the HIV
protease inhibitors where the lead compound was the substrate). At the end of this lecture
the student will know the concepts of therapeutic index and of the pharmacophore, based
on the opioids, and the traditional methods used for optimization of lead compounds to
improve their biological activity.
Oral contraceptives are an example
biochemical pathway: regulation of menstration and pregnancy
steriods (e.g. progesterone) identified as mediating compounds; therefore
used as lead compounds
modification of physiological steroids leads to active agents
(contraceptives)
Figure 1) Structures of progesterone and (+)-norgestrel
Therapeutic index (therapeutic ratio)
measure of the ratio of undesirable to desirable drug effects (multiple
bioassays)
in vivo: LD50/EC50 = therapeutic index
LD50: the lethal dose for 50 % of the test animals
EC50: the effective dose that produces the maximum therapeutic effect in
50% of the test animals
, MacKerell, Lead Modification 2
the larger the therapeutic index the greater the safety of the drug: goal of
lead optimization
Pharmacophore (similar to SAR with sulfa drugs)
Functional group types (e.g. hydrogen bond donors, acceptors, hydrophobic regions) and
the spatial arrangement of those groups on a molecule that interact with the receptor and
are responsible for binding and biological activity.
Ideally separate the binding pharmacophore from the activity pharmacophore to design a
compound that binds but does not cause the biological activity (antagonist). For
example, with the opioids, determine the individual pharmacophores for the analgesic
and addictive properties.
First identify the pharmacophore and then design compounds that systematically deviate
from the pharmacophore to obtain desired efficacy.
Pharmacophore identification via functional group modification
1) systematically alter or remove portions of the molecule
2) identify regions essential for activity (or different types of activities)
3) note that pharmacological data is sometimes ambiguous (i.e. data is not
clear cut yes or no, but often somewhere in between), requiring care when
interpreting relationships of structure to activity.
Opioids as an example (morphine)
Note that physiological substrates for opioid receptors were not known for many
years (endorphins, enkephalins, dynorphins and others).
Figure 2) Structure of morphine, codeine and heroin
1) Remove tetrahydrofuran ring and hydroxyl at R'
