Transcript Drug Discovery & Development PHC 311 LEC. 3 Sunday 9/ 11/ 1434H

Drug Discovery & Development
PHC 311
LEC. 3
Sunday 9/ 11/ 1434H
Drug Optimization:
Strategies in drug design
I-optimizing drug target interactions
• Drug optimization aims to maximize the interactions of a
drug with its target binding site in order to improve activity,
selectivity and to minimize side effects.
• Designing a drug that can be synthesized efficiently and
cheaply is another priority.
• The aim of drug optimization can be achieved by different
strategies or approaches on the lead compound SAR, such
as;
2
General approach
• 1- Molecular disjunction (molecular dissociation,
dissection or simplification)
• 2- Molecular conjunctive approach
a- Molecular addition
b- Molecular replication
c- Molecular hybridization
II. Special approach
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1. Ring closure or ring opening
2. Ring expansion and ring contraction
3. Homologation and chain branching
4. Introduction of unsaturation center
5. Introduction, removal or replacement of bulky
groups
6. Changes of substitution position
7. Introduction of chiral center
8. Conformation restriction (molecular rigidification)
9. Isosteres and bioisosteres
1. Ring closure or ring opening
• Diethylstilbesterol may be regarded as a ``ring
opening`` modification of estradiol
• Closure of a chain or opening of a ring
• Ring chain transformation has important pharmacokinetic
effect as it increase the lipophilicity and decrease the
metabolism. So this makes the drug more active in vivo.
2. Ring expansion and ring
contraction
3. Homologation
• A homologous series is a group of compounds that
differ by a constant unit, generally a CH2 group.
This phenomenon corresponds to
Increased lipophilicity of the molecule to permit penetration into
cell membranes until its lowered water solubility becomes problematic in its
transport through aqueous media.
In the case of aliphatic amines
Micelle formation is a problem which begins at C12. This effectively
removes the compound from potential interaction with the receptors.
e.g. 1: Hypnotic activity of alcohols


The maximum effect occurred for 1-hexanol to 1-octanol.
The potency declined on chain lengthening until no activity was
observed for hexadecanol.
e.g. 2: 4-alkyl substituted resorcinol derivatives
[Antibacterial effect is maximum in case of 4-n-hexyl resorcinol]
Chain branching
• Chain branching decrease the potency.
• The branched side chain is less lipophilic than
the straight one.
• The branched chain may interfere with:
- ADME.
- Receptor interaction.
Chain branching
in case of [Homologation]
lipophilic relationship is important
Chain branching lowers the potency of a compound
because a branched alkyl chain is less lipophilic
than the corresponding straight alkyl chain.
The lowered potency may be due to
 pharmacokinetics
(Absorption, metabolism, excretion,……..etc.)
 pharmakodynamics
Chain branching may interfere with receptor binding
e.g. 1: Phenyl ethyl amine
NH2
NH2
(amphetamine)
[It is a poor substrate for MAO]
It is an excellent substrate for
monoamine oxidase
e.g. 2: Primaquine
is more potent than its secondary or tertially amine analogues.
CH3O
N
H2N
NH
CH3
Primaquine
[Antimalarial]
e.g. 3: 10-aminoalkylphenothiazines
S
S
N
N
N
CH3
N
CH3
CH3
CH3
CH3
Promazine
Promethazine
Antispasmotic and antihistaminic have greatly
reduced and sedative and tranquilizing activities
are greatly enhanced
Antispasmotic and antihistaminic
S
N
N
CH3
CH3
CH3
Trimeprazine
The tranquilizing activity reduced and
antipruritic (anti-itch) activity increased
These examples indicate that multiple receptors are involved for 10-aminoalkyl
phenothiazines. Branching or homologation can cause the molecule to bind more or
less well to the receptors responsible for antispasmodic, antihistaminic, tranquilizing,
or antipruritic activities.
4. Introduction of unsaturation center
• The introduction of an unsaturated group (vinyl, allyl,
ethenyl, ethynyl……….etc) in a drug molecule alters
its stereochemistry and physicochemical properties
and consequently affects its biological activity.
• The increase in hypnotic activity of ethylene
(general anaesthetic) than the saturated
derivative
5. Introduction, removal or replacement
of bulky groups
• This special process is used mainly to:
• Convert agonist to antagonist or
• Prevent the enzymatic degradation
6. Changes of substitution
position
• The position of certain groups is sometimes
essential for given biological for a given biological.
• For example, the three isomers of hydroxybenzoic
acid only the o-hydroxy is active, because it can
form an intramolecular hydrogen bond and, in this
way, it can act as a chelating agent.
7- Introduction of chiral centers
• Receptors are chiral entities and the interactions of
many drugs at specific sites chirality of interaction.
• Introduction of chiral centers can alter drastically its
pharmacological activity.
• e.g.
• the four isomers of choramphenicol, only the D-(-)threo-form is active.
• L-(-)-ascorbic acid has antiscorbutic activity wherease
(+) ascorbic does not.
• R(-)-isomer of epinephrine is more potent on both αand β- adrenergic receptors than the S(-)-isomer.
8- Conformation restriction
(molecular rigidification)
• The antimigrain, sumatriptan, undergoes rapid
oxidative metabolism of the aminoethyl side
chain to the inactive indolacetic acid.
Conformmational restriction to give the cyclic
piperidine analogue retains the antimigraine
activity, but has much longer duration.
• The simple addition of α-methyl group to give
ACE inhibitor captopril increased by 10-folds
over the des-methyl compound.
Extension of Structure
 Add extra binding groups to search for nearby binding sites. As a result,
we may increase the binding affinity of the drug with binding site
 By increasing the interactions of the drug with binding site, we could
prevent the natural substrate from binding (antagonist)
Increase rigidity and/or structural complexity
Etorphine
-two-carbon bridge
-substituent not in morphine
-1000x more potent than morphine
- used in veterinary medicine to
tranquilize large animals
CH3
HO
R'
R
Etorphine: R = CH3, R' = C3H7
N
Buprenorphine: R =
O
Buprenorphine
-10 - 20 times more potent than morphine
- Low addictive potential
- recently indicated as a therapeutic agent
for the treatment of heroin addiction
rigidity increases potency
OH
OCH3
CH2
R' = tert-butyl
• Rigidification is used on flexible lead
compounds. The aim is to reduce the number
of conformations available while retaining the
active conformation. Locking Rotatable rings
into ring structure or introducing rigid
functional groups are common methods of
rigidification.
9. Isosteres and Bioisosteres
Why..?
Bioisosterism
• Bioisosterism is a lead modification approach
that has been
• shown to be useful to attenuate:
• Toxicity
• Modify the activity of a lead
• May have a significant role in the alteration of
• metabolism of the lead
Parameters affected with
isosteric replacement
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Size
Conformation
Polarity
H-Bond formation
Solubility
Hydrophobicity
Reactivity
Classification of isosteres
1- Classical.
2- Non-classical.
Classical Bioisosteres
1.
2.
3.
4.
5.
Monovalent atoms and groups (C, N, O, S)
Divalent atoms and groups (R-O-R, R-NH-R, )
Trivalent atoms and groups (R-N=R, R-CH=R)
Tetrasubstituted atoms ( =C=, =N=, =P=,)
Ring equivalents
Nonclassical Bioisosteres
1. Exchangeable groups
2. Rings versus noncyclic structures
The nonclasical bioisosteres do not rigidly fit the steric and
electronic rules of the classical bioisosteres
Thank you