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DRUG DESIGNDr. Bilal Al-Jaidi
Introduction
Medicinal Chemistry is the science that deals with the design and developmnet of new pharmaceutical agents.
Medicinal Chemist interests in: 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
Drug Discovery
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.
Clinical trials
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.
Clinical trials
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.
Lead compound
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.
Drug candidate and clinical drug
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.
Lead Discovery
Is the first step in drug discovery.
You can not discover a lead if you do not have: 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.
Sources of the lead
1. If the biological target is known, then the lead compound will be the natural ligand of this receptor or enzyme
Adrenaline
HO
HO
NH2
OH
H
Noradrenaline
HO
HO
HN
OH
H
O
O
N
Acetylcholine
Lead for cholinergic agonistAnd antagonists
Leads for adrenergicAgonists and antagonists
Sources of the lead
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: 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
Sources of the lead
4. Non-random screening: in this approach the tested compounds having some structural similarity to a weakly active agents.
5. Drug metabolism studies:N
OHPh
Ph
OH
Terfinadine
N
OH
COOH
Ph
Ph
OH
Fexofinadinemore activeLess sedating antihistaminic agent
NN
OOH
Cl
NN
OOH
Cl
Hydroxyzine Cetirizine
O
Sources of the lead
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 anti-
allergic agents, but they exhibited a good activity in treating motion sickness.
Lead modification
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
Pharmacophore and Auxophore
Auxophore: is the groups rather than the pharmacophore in the chemical structure.
Many roles have been identified for the auxophore: Hold the pharmacophoric groups in their
place. Interfere with the binding to the receptor…un-
favorable. Occupy an inert space. Affect the pharmacokinetic properties of the
whole structure.
Example of the study of pharmacophore
The pharmacophoric groups in opioid analgesics are shown below (Bold style):
the other groups (not in the bold style) are auxophoric group.
O
N
HO
OH
Morphine
O
N
HO
OH
Morphine
N
HO
OH
Levorphanol4X more potent as analgesicaddiction still possible
N
HO
PentazocineLower addiction liability
N
HO
Still an effective analgesic
the removal of the tetrahydrofuran ring did not affect the overall bioactive conformation of the compound
Lead modification
The second step in the lead modification is the functional group modification depending on the study of the pharmacophore.
Example: sulfonamide lead modification:SNH
O O
H2N
NH
O
CarbutamideHas antibacterial and hypoglycemic activity
SNH
O O
NH
O
TolbutamideHas only hypoglycemic activity (WHY??)
Lead modification
The second step in the lead modification is the functional group modification depending on the study of the pharmacophore.
Example: sulfonamide lead modification:SNH
O O
H2N
NH
O
CarbutamideHas antibacterial and hypoglycemic activity
SNH
O O
NH
O
TolbutamideHas only hypoglycemic activity (WHY??)
This is the antibacterialpharmacophore
This is the hypoglycemicpharmacophore
Lead modification
The third step is to construct the structure activity relationships.
Drugs can be classified into: 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
Structural modification
The main aim is to get more active, potent and safer agents compared to the lead compound.
Methods for structural modification: 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.
OH
OH4-hexylresorcinoltopical anesthetic
Chain branching: alkyl branching will lower the lipophilicity. Alkyl branching will weaken the binding with the
biological target.
Ring chain transformation: Affects both lipophilicity and drug metabolism
NH2
PhenethylamineMAO substrate
NH2
AmphetaminePoor substrate for MAO
N
O
O
Arecoline
N
O
O
Acetylcholine
Bioisosterism: Bioisosteres are groups or substituents that have
chemical or physical similarities which produce similar biological activity.
Importance of the use of Bioisosteres:
Alter the pharmacokinetic properties. Attenuate toxicity. Modify activity. Potentiate activity.
Two types of Bioisosteres: Classical Bioisosteres. Non-classical Bioisosteres.
Classical Bioisosteres
Are atoms or molecules in which the peripheral layers of electrons can be considered identical.
Subclasses: 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-
Classical Bioisosteres
Trivalent: -CH= , -N= Tetravalent:
Ring equivalent:
C Si
C N
S
N
OHN S
Non-Classical Bioisostere
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: OH
OS
OH
O OS
NH2
O O NO
OH
OH NHCN
X CF3 CN
NNO2
CH2 3
Structural modification to improve oral bioavailability
Factors affecting oral bioavailability:
Physicochemical stability. Biological stability:
Effect of intestinal enzymes. First pass metabolism.
Lipophilicity. Extent of ionization.
Lipophilicity
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 Octanol was selected because it simulates the
lipophilic membrane; lipophilic and sparingly soluble in water
Lipophilicity
Ionized drug will have lower lipophilicity than the neutral form.
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
Example of logD
LogD pH-1.31 2.00.12 7.51.73 10.0
ONH
OH
OMetaprolol
Prediction of lipophilicity
To predict the lipophilicity, we must know the lipophilicity of substituents.
Lipophilicity substituent constant (π)
Π = logPX –LogPH (Hansh approach)
Substituent or fragment constant
Example
Calculate the logP of Aspirin:
logP = 1.67-0.03-0.61-1.09+0.89 = 0.83
OH
O
O
O
Other factors affecting lipophilicity
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
OHOH
Methanol Phenol
Methanol is more polar, less lipophilic than phenol
Effect of Ionization
Extent of ionization of drugs may affect the following:
Lipophilicity. Oral availability. Receptor-drug interaction. Excretion. Distribution
Effect of Ionization
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?)
Example
NNHO
PhenylbutazonepKa = 4.5Unionized in urinelow effect as uriccosuric agent
NNHO
SOO
pKa = 2.8better ionized in urinebetter action as uricosuric agent
Example
SNH
O O
H2N
NO S
N
O O
H2N
NO
unionizedimportant for getting into the bacterial cell
(important for pharmacokinetics)
Ionizedimportant for eznyme interaction
(important for pharmacodynamics)
Lipinski’s rule of five
The orally administered drug must not have: A molecular weight > 500 Dalton LogP > 5 H-bond donor > 5 H-bond acceptor > 10
There are some exceptions out of this rule: Drugs that have specific transporters such as
peptidomimetic agents. Drugs targeting CNS should have:
H-bond donor ≤ 3 H-bond acceptor ≤ 6
Veber findings
For better oral availability, drug candidate must have:
Rotatable bonds ≤ 10 Polar surface area ≤ 140 A°2
Total hydrogen bond count ≤ 12
Ajay findings
For drugs targeting CNS:
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.
If the aromatic density, no. of H-bond donors or logP is increased, the compound is more likely to be CNS active.
Some Exceptions
O
NHN
O
S
O
HO
H
NH2
cephalexin
O
NHNH
O
SH
OHO
H
NH2
D-Phe-Cys-Val
HNN
OO
NHN
OH2N
HNO
NH
N
O
O
NNH
O
NH2
TRH
Gln-His-Pro
NH
O
N
OHO
O O
Enalapril
NH
O
N
OHO
NH2O OH NH2
O
Phe-Ala-Pro
resembles resemblesresembles
This can be benefial
HN
N N
N
O
H2N
O OH
HN
N N
N
O
H2N
O O
O
NH2
AcyclovirValacyclovir
Valacyclovir will have better oral availability although it is more polar than acyclovir because it will absorbed by the peptide transporter from the intestine