Transcript Medicinal Chemistry

Medicinal Chemistry
Is the science that deals with the
design
and
development
of
pharmaceutical agents that has a
desired biological effect on human
body and other living systems.
Drug
• Is a compound that interact with a biological
target to produce a biological response:
– Biological target: Human, bacteria, fungi,…
– Biological response: desired or undesired.
• Sugar, salt, pesticides, herbicides, can be
considered as drugs.
• Food and fizzy drinks also considered as drugs.
• Medicinal chemists concern
about the synthesis of new
molecules to investigate the
relationships
between
the
chemical structure of these
compounds and their biological
activities.
Medicinal chemistry also involves isolation
of compounds from natural sources
The Ideal drug must be:
–Not toxic.
–Effective and potent.
–Selective.
–Easily administered.
–Cheap
In Reality, There is no Ideal drug.
• Penicillin: one of the safest and most active
antibiotics……BUT….. Resistance developed to
most of them.
• Morphine: a very effective pain killer….. BUT….
May cause tolerance, addiction and respiratory
depression.
• Heroin: the best pain killer we know….BUT….
addiction developed (still used in terminal
cancer).
• Drug might be harmful at higher doses:
– Therapeutic index: it is the ratio of the dose
leads to toxic effect in 50% of cases to that
leads to therapeutic effect in 50% of the cases.
Large therapeutic index…… safer drug.
narrow therapeutic index…… more toxic
drug.
– Poisons can be drugs at lower doses:
 Arsenicals: very toxic but used as
antiprotozoal agents.
Tubocurarine: used as muscle relaxant.
Selective Toxicity
• Selective Drugs: that show toxicity against abnormal
cells without affecting normal cells.
• Degrees of selectivity:
– No effect on normal host cells.
– Killing certain microbial strain without affecting others.
– Targeting certain metabolic pathway without affecting
others.
Drug Targets
• they are macromolecules (receptors, enzymes,
DNA or transport proteins).
• Drugs interact and bind to the binding sites
through intermolecular bonds (ionic, H-bonds,
Van Der Waals, dipole-dipole and hydrophobic).
• The bonds mainly are weak, therefore in most of
the cases this binding is reversible.
Human FAS
Orlistat
In medicinal chemistry:
• Pharmacokinetic: How the drug distribute and
reach its target (ADME) and what will happen to
the drug
• Pharmacodynamic: How the drug interact with its
target.
• Pharmacokinetics – what the body does to
the drug:
–How does drug get it into the body?
–How long does it take to exert its
action?
–How long does it stay in the body?
–Where does it go to in the body?
–Is it metabolised to another form?
The [plasma]-time curve after drug
administration
Pharmacokinetics
Which route?
Which formulation?
Drug administered
Drug absorbed
Metabolic
inactivation
Which barriers to cross?
Gut, skin, lungs?
Stability at the site of absorption?
Pool of non-available
Drug in the tissues
•Plasma-protein binding?
• Electrostatic charge
•Tissue-protein binding?
•Fat storage?
available
Drug in the plasma
Passive diffusion?
Active transport?
Blood-brain barrier penetration?
Drug at the site
of action
Excretion
Pharmacokinetic properties
ADME
Pharmacokinetic properties
• Drug administration: How is the drug to be
formulated? If as an injection, is it soluble in
aqueous solution? If as a tablet, will it dissolve
when released in the gut?
• Drug absorption: can the drug pass through the
barrier membranes in the GIT? Can it pass
through the skin barriers? These barriers are
made up in a large part by lipids, so the drug
must be sufficiently lipophilic/ unionized to
diffuse through them.
• Membranes have phospholipids bilayer that act as
barriers to the movement of drugs within the body
Pharmacokinetic properties
• Drug metabolism: metabolism increases the
water solubility of drugs by enzymatically
introducing polar functional groups so that they
can be excreted: what is the chemistry of the
drug? How fast is it inactivated? Is it converted
into more active or even toxic components?
• Drug excretion: the kidney excretes water-soluble
metabolites and the ionized forms of drugs.
*
• Pharmacodynamics – what the drug does to the
body:
– What is the therapeutic effect of the drug?
– How does it exert its effect?
– How does the drug interact with the target?
– Can the effect be modified?
• More than 90% of drugs have biological
targets to bind with in order to exert their
pharmacological effects.
– Biological targets: are endogenous
macromolecules including DNA, RNA,
enzymes, receptors, membrane proteins,
etc…
DNA
Protein
The nature of drug-receptor binding
• Either reversible or irreversible.
• Reversible binding means that the drug-target
complex will dissociate to release the free
functioning target.
• Irreversible binding means permanently blocking
the binding site of the target… irreversible
damage.
Interactions involved in drug-receptor
interaction
• Includes:
Ionic bonding
Hydrophobic
interaction
Dipole-dipole
interaction
Aromatic
interaction
Hydrogen bonding
Pharmacokinetics and
Pharmacodynamics: are they
inter-related?
The answer is definitely yes
• If for a reason or another the drug will not reach
the target, no pharmacological effect will be
observed even if the drug is known to effectively
bind to the target active site.
• If the drug has a proper pharmacokinetic
properties and deposited in enough
concentration around the site of action, it must
effectively bind to the target to exert its biological
effects
*
What do we mean by:
Oral
availability
Oral
stability
Tissue
availability
Oral
activity
What do we mean by:
Oral
availability
Oral
stability
Tissue
availability
Oral
activity
Oral
availability
• Oral availability or bioavailability measures the
fraction of the drug being absorbed into the
blood circulation.
• Factors affecting oral availability:
– Chemical nature of drug (lipophilicity and
ionization state).
– Water solubility.
– Oral stability.
– Physiological factors.
Oral
stability
• Oral stable drugs must be:
– Chemically stable toward the GIT conditions; acidic
stomach and basic intestine.
– Enzymatically stable (first-pass metabolism): stable
toward the digestive and metabolizing enzymes such
as esterase, amidase and oxidase enzymes.
• If the drug is orally unstable it will not be
available to be absorbed…..low oral availability.
Oral
stability
• First pass metabolism does not mean only liver
metabolism of orally administered drugs before
the drug being deposited in blood.
• It covers all metabolic transformation happened
to the drug after oral administration before
reaching the systemic circulation.
Oral
stability
• First pass metabolism includes:
– All Oral cavity enzymes such as amylase and lingual
lipase
– Stomach pepsinogen
– All GIT proteolytic enzymes.
– All Intestinal hydrolase enzymes such as esterase,
amidase and carbohydases.
– All intestinal lipases and reductase enzymes.
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Oral
availability
Oral
stability
Tissue
availability
Oral
activity
Oral
availability
Oral
stability
Tissue
availability
Oral
activity
Orally
activity
• Orally active agents are drugs either active locally
in the GIT lumen (such as in the case of
gastroenteritis) or must be absorbed into the
blood circulation.
• Factors affecting oral activity:
– Chemical and enzymatic stability of drugs.
– The physiological nature of the GIT lumen.
– The same factors affecting the oral availability in the
case of systemically active agents.
Orally
activity
• Systemically active agents must be stable in the
GIT as well as during the first pass metabolism if
reaching the liver before the blood circulation.
• The locally acting agents must be just stable in
the GIT, it does not necessarily absorbed through
intestinal membrane, they will just act locally:
– Given in active form.
– Given as prodrug…activated in GIT by special
enzymatic reactions
Orally
activity
• Example:
– Paromomycin is one of the aminoglycosides that is
widely used in GIT infections caused by
salmonella, Shigella and Amoeba.
– It is active after oral administration
although it has a very limited oral
absorption (highly polar compound).
– It will only work locally.
Orally
activity
• Example:
– Sulfasalazine; a commonly used drug in ulcerative
colitis, although it will be given orally, small
quantity will be absorbed.
– It will be reduced by colorectal azoreductase to
give the active sulfapyridine and P-aminosalicylic
acid…both are active
Tissue
Availability
• Tissue availability means the amount of the drug
that reached the site of action or the target
tissue.
• In most cases, tissue availability is lower than the
oral availability due to one of the following
factors:
–
–
–
–
–
Extensive drug metabolism.
Blood protein binding.
Rapid drug excretion.
Fat deposition of drug.
Many barriers to penetrate to reach the site of action.*
The molecular properties of drugs
• It is the physicochemical properties of drugs.
• These properties fundamentally affect every
thing the drug does to the body (the
pharmacodynamic aspects) and what the body
does to drugs (the pharmacokinetic aspects).
• the molecular properties also determine which
dosage form and the route of administration is
suitable for the given drug.
Molecular properties of interests
1.
2.
3.
4.
5.
Partition coefficient.
Dissociation constant (degree of ionization).
Solubility (aqueous and fat solubility).
Chemical stability.
Biological stability (metabolic profile of
drugs).
Drug solubility
• Is drug soluble enough in the GIT content?
• Is it soluble enough in blood to be given
parenterally?
• More water soluble drug in blood….large volume
of distribution.
• More water soluble drugs…poor penetration into
CNS through the lipophilic blood brain barrier.
• More water soluble drugs…poor penetration into CNS
through the lipophilic blood brain barrier.
• As a result, very limited number of drugs can act on
CNS.
Pores
Physicochemical properties of drugs
•
Partition coefficient
• Lipophilicity/hydrophilicity
•
Ionisation/dissociation constant
• Strong or weak acids/bases
• Salt formation
•
Solubility
• Water-soluble salts
• Lipid soluble esters
•
•
•
Stability
Chemical degradation – oxidation, hydrolysis, light
Enzyme degradation (metabolism) esterases, amidases,
cytochrome P450
*
Lipophilicity/hydrophilicity of drugs
Acceptor
H
O
H
CH3
H
O
Donor
O
H
Acceptor
H
O
Donor
Partition coefficient
• Is the measurement of the drug water solubility.
• Partitioning means that the drug will be divided in parts
between the water and the oil layer.
–
–
•
•
•
•
•
P = [Co ]/[Cw]
LogP = Log[Co ]/[Cw].
LogP > 2 lipophilic drug.
LogP < 2 hydrophilic drug
LogP only applied to neutral compound
Low logP….. Low penetration to CNS
High logP….. Low water solubility…. Not suitable for oral
administration
Partition coefficient and drug
ionization
• Once the drug become ionized, its partitioning
will definitely be changed since it will be more
polar, water soluble than the neutral form.
• This is very important to keep in mind when
administering drugs that will be ionized in GIT,
because this will affect their absorption.
PARTITIONING OF ACIDS AND BASE
For an acid substance
Papp
•
•
•
P

pH  pKa
1  10
For a base substance
Papp
P

1  10 pKa  pH
Papp is the apparent partition coefficient, which varies with pH,
For acids, at pH values below the pKa, Papp = P, since ionization is
suppressed and the drug is only in unionized .
At pH values above the pKa the value of Papp decreases because the
species is ionizing and moving into the aqueous layer.
An example about the relation between the Papp and P :
Consider drugs that are acids, for example RCOOH, which has a pKa of 4.0, and
a Partition coefficient of 200.
Biological
Membrane
Gut Contents
In stomach
In intestine
H
RCOOH
+
RCOO
RCOOH
X
Drug Absorption
No Drug
Absorption
•
Papp becomes 198 in the stomach suggesting that absorption will take
place
•
pH 8.0 in the small intestine, the calculated Papp suggests no absorption.
• 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
2.0
0.12
7.5
1.73
10.0
By lowering the
pH
Ionization
increases
Basic group with
a Pka of 10
*