Dr. Bilal Al-Jaidi
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Medicinal Chemistry is the science that deals
with the design and developmnet of new
pharmaceutical agents.
Medicinal Chemist interests in:
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The synthesis of drugs.
The isolation of natural products.
Establishing the structure activity relationships of
the compounds.
Studying the drug-target interaction.
The pharmacokinetic profile of drugs
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Drug discovery is a costly and time consuming
process… from 10000 obtained compounds,
only one will reach the market.
After establishing the safety and efficacy of the
designed compound on laboratory animals,
clinical trials must be applied on human.
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Phase-I (lasts for 1 month -1 year): evaluate the
safety, tolerability, pharmacokinetic and
pharmacological activity of drugs on 20-100
volunteers.
Phase-II (lasts for 1-3 years): further assess the
efficacy , safety of drugs in addition to dosing
regimen in 300-600 patients.
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Phase-III (last for 2-6 years): covers several
thousands of patients in clinics or hospitals;
study the activity and possible side effects on
the long term.
Phase-IV: it is the post marketing feedback,
after prescribing drugs to the out patients.
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Is a prototype compound that has many
attractive properties, most importantly, good
activity, stability and suitable
pharmacokinetics.
Lead optimization is to modify the chemical
structure of the lead compound in order to
improve the desired properties and trying to
minimize the unwanted ones.
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Drug candidate: is that drug obtained from the
lead optimization experiment….needs
extensive studies to be clinically available.
Clinical drug: compound that is ready for
clinical trials.
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Is the first step in drug discovery.
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You can not discover a lead if you do not have:
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A well established bioassay…that will study the
efficacy and potency of compounds.
High throughput screening and ultra high
throughput screening.
Enzymatic assay.
Instrumental analysis such as MS and NMR to
interpret the bioassay results.
1. If the biological target is known, then the lead
compound will be the natural ligand of this
receptor or enzyme
Leads for adrenergic
Agonists and antagonists
Lead for cholinergic agonist
And antagonists
2. The marketed drugs can be used as lead
compounds.
3. Random screening: this approach is used if we
do not know the biological target:
examples:
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the sulfa drug; sulfanilamide was used as the lead
for the development of many sulfa drugs.
Aminoglycosides and tetracyclines were discovered
after random screening of soil samples on different
bacterial strains
4. Non-random screening: in this approach the
tested compounds having some structural
similarity to a weakly active agents.
5. Drug metabolism studies:
6. From clinical observations: in this case the drug
candidate exhibits more than one
pharmacological action:
Examples: (Drugs off Label)
 Sildenafil was designed for anti-hypertensive action
but found to improve the erectile function.
 Buclizine and Meclizine first synthesized as antiallergic agents, but they exhibited a good activity in
treating motion sickness.
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The aim here is to improve the desired properties
in the lead compound and try to reduce the toxic
or un favorable effects.
The first step in this process is to identify the
PHARMACOPHORE.
Pharmacophore is a collection of groups in the
molecule that interact with the receptor or the
enzyme and are responsible for activity
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Auxophore: is the groups rather than the
pharmacophore in the chemical structure.
Many roles have been identified for the
auxophore:
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Hold the pharmacophoric groups in their place.
Interfere with the binding to the receptor…unfavorable.
Occupy an inert space.
Affect the pharmacokinetic properties of the whole
structure.
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The pharmacophoric groups in opioid
analgesics are shown below (Bold style):
the other groups (not in the bold style) are
auxophoric group.
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The second step in the lead modification is the
functional group modification depending on
the study of the pharmacophore.
Example: sulfonamide lead modification:
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The second step in the lead modification is the
functional group modification depending on
the study of the pharmacophore.
Example: sulfonamide lead modification:
This is the antibacterial
pharmacophore
This is the hypoglycemic
pharmacophore
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The third step is to construct the structure
activity relationships.
Drugs can be classified into:
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Structurally specific: here the drug binds to specific
site (receptor, enzyme, DNA,…etc).
Structurally non-specific: drug has no specific site to
bind with in order to exert its pharmacological effect
(such as gaseous anesthetics, disinfectants and most
of sedative hypnotics)
Structurally specific drugs are more potent
than structurally non-specific ones
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The main aim is to get more active, potent and
safer agents compared to the lead compound.
Methods for structural modification:
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Homologation: is to lengthen the alkyl chain in the
chemical structure by CH2:
 Chain length up to 9 carbon atom….tolerable (optimum
lipophilicity and water solubility.
 Chain length more than 9 carbon atoms…low water
solubility… low availability.
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Chain branching:
 alkyl branching will lower the lipophilicity.
 Alkyl branching will weaken the binding with the
biological target.
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Ring chain transformation:
 Affects both lipophilicity and drug metabolism
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Bioisosterism:
 Bioisosteres are groups or substituents that have
chemical or physical similarities which produce similar
biological activity.
 Importance of the use of Bioisosteres:
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Alter the pharmacokinetic properties.
Attenuate toxicity.
Modify activity.
Potentiate activity.
 Two types of Bioisosteres:
 Classical Bioisosteres.
 Non-classical Bioisosteres.
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Are atoms or molecules in which the peripheral
layers of electrons can be considered identical.
Subclasses:
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Univalent:
CH3 , NH2 , OH , F , Cl
Cl, SH
Br, i-Pr
I, t-Bu
Divalent:
-CH2- , -NH- , -O- , -S-CO-CH2- , -CO-NH- , -CO-O-, -CO-S-
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Trivalent:
-CH= , -N=
Tetravalent:
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Ring equivalent:
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They do not have the same no. of atoms…this
means that the size, shape and electronic
properties are different…at the same time they
have the same impact on biological activity.
Examples:
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Factors affecting oral bioavailability:
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Physicochemical stability.
Biological stability:
 Effect of intestinal enzymes.
 First pass metabolism.
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Lipophilicity.
Extent of ionization.
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The orally administered drug must have
moderate lipophilicity (logP = 2-5) in order to
absorbed through the lipophilic mucus
membrane.
It is recommended that one can predict the
lipophilicity of the chemical compound before
start synthesizing it.
P = [C]octanol /[C]water
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Octanol was selected because it simulates the
lipophilic membrane; lipophilic and sparingly
soluble in water
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Ionized drug will have lower lipophilicity than
the neutral form.
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is the degree of dissociation in water, depends on
the ionization constant.
LogD: is the log of distribution coefficient that
describe the lipophilicity of ionizable
compound
LogD
pH
-1.31
2.0
0.12
7.5
1.73
10.0
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To predict the lipophilicity, we must know the
lipophilicity of substituents.
Lipophilicity substituent constant (π)
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Π = logPX –LogPH (Hansh approach)
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Calculate the logP of Aspirin:
logP = 1.67-0.03-0.61-1.09+0.89
= 0.83
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Branching: logP will be lowered by 0.2 per
branch.
Inductive effect of electron withdrawing
groups.
Resonance effect: if it will affect the possibility
of H-bonding.
Example
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Extent of ionization of drugs may affect the
following:
Lipophilicity.
 Oral availability.
 Receptor-drug interaction.
 Excretion.
 Distribution
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At a given pH, there is an equilibrium between
the ionized and unionized form.
Only the unionized form will be absorbed from
the GIT.
The equilibrium between the ionized and
unionized will be reestablished to generate
unionized drug again for absorption (what are
the factors affecting this equilibrium?)
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The orally administered drug must not have:
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A molecular weight > 500 Dalton
LogP > 5
H-bond donor > 5
H-bond acceptor > 10
There are some exceptions out of this rule:
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Drugs that have specific transporters such as
peptidomimetic agents.
Drugs targeting CNS should have:
 H-bond donor ≤ 3
 H-bond acceptor ≤ 6
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For better oral availability, drug candidate
must have:
Rotatable bonds ≤ 10
 Polar surface area ≤ 140 A°2
 Total hydrogen bond count ≤ 12
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For drugs targeting CNS:
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If the molecular weight, the degree of branching, the
no. of rotatable bonds or the no. of H-bond acceptors
increased, the compound will less likely to be CNS
active.
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If the aromatic density, no. of H-bond donors or logP
is increased, the compound is more likely to be CNS
active.