Prodrugs IIProdrugs II
Prepared ByPrepared By Professor Mohamed Ahmed MoustafaProfessor Mohamed Ahmed Moustafa
Professor of Medicinal ChemistryProfessor of Medicinal Chemistry
DRUG DRUG TARGETINGTARGETING
Site-specific drug delivery attempts to obtain very Site-specific drug delivery attempts to obtain very
precise and direct effects at the precise and direct effects at the ‘‘site of actionsite of action’’ withoutwithout
subjecting the rest of the body to significant levels of the subjecting the rest of the body to significant levels of the
active agent. active agent.
Prodrugs for Site Specificity
The targeting of drugs for a specific site in the body by conversion to
a prodrug is plausible when the physicochemical properties of
prodrug are optimal for the target site.
It should be kept in mind, however, that when the lipophilicity of a drug is
increased, it would improve passive transport of the drug nonspecifically to all
tissues.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site SpecificityTo increase the site specificity of certain drugs, the To increase the site specificity of certain drugs, the
following means of preparing prodrugs are used:following means of preparing prodrugs are used:
1.1. Increase or reduction in volumeIncrease or reduction in volume
2.2. Alteration of hydrophilicity or solubilityAlteration of hydrophilicity or solubility
3.3. Introduction or removal of cationic or anionic moietiesIntroduction or removal of cationic or anionic moieties
4.4. Change of pKaChange of pKa
5.5. Incorporation of hydrocarbon or other suitable stable Incorporation of hydrocarbon or other suitable stable or labile moieties, and carriers that transport the or labile moieties, and carriers that transport the compound to specific organs or tissues and make it to compound to specific organs or tissues and make it to accumulate selectively there, where it is bioactivated.accumulate selectively there, where it is bioactivated.
Prodrugs for GITProdrugs for GIT
A nice objective of using prodrugs is to restrict the drug A nice objective of using prodrugs is to restrict the drug
action to the upper part of the action to the upper part of the GIT GIT
If we want to target drugs against an infection of the If we want to target drugs against an infection of the GIT, then we want to prevent the drugs being GIT, then we want to prevent the drugs being absorbed into the blood supply. absorbed into the blood supply.
How??How??
Retardation of the drug absorption, as in case of Retardation of the drug absorption, as in case of
sulfathiazolesulfathiazole
How would you decrease the absorption of this How would you decrease the absorption of this
drug?drug?
This can easily be done by using a fully ionized This can easily be done by using a fully ionized molecule which is incapable of crossing cell molecule which is incapable of crossing cell membranes.membranes.
The incorporation of strongly The incorporation of strongly hydrophilic moietieshydrophilic moieties
to the sulfonamides prevents their transport to the to the sulfonamides prevents their transport to the
bloodstream.bloodstream.
They are incapable of crossing the gut wall and are They are incapable of crossing the gut wall and are therefore directed efficiently against the GI therefore directed efficiently against the GI infection.infection.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
used as intestinal antibacterial agent.used as intestinal antibacterial agent.
These prodrugs act almost exclusively inside the intestinal tract.
The succinyl or phthalyl group is good enough to decrease
lipophilicity of the compound.
The hydrophilic group makes the molecule poorly absorbed,
preventing its transportation to the circulation.
N
SNH
S
NO O
H
OOHO
Prodrugs for (increased) Site Prodrugs for (increased) Site SpecificitySpecificity
BitolterolBitolterol, , a prodrug of the a prodrug of the -blocker -blocker
colterolcolterol.. The toluate groups in both aromatic hydroxyls The toluate groups in both aromatic hydroxyls
prevent the methylation of one of the groups prevent the methylation of one of the groups
by the enzyme COMT, until these groups are by the enzyme COMT, until these groups are
removed by hydrolysis by the esterases removed by hydrolysis by the esterases
present in the tissues and in the blood.present in the tissues and in the blood.
Bitolterol accumulates selectively in the Bitolterol accumulates selectively in the lungslungs, ,
where it partially and immediately releases where it partially and immediately releases
colterol, which stimulate colterol, which stimulate -adrenergic -adrenergic
receptors and then adenylatic cyclase, with receptors and then adenylatic cyclase, with
the consequent relaxation of the bronchial the consequent relaxation of the bronchial
smooth muscles.smooth muscles.
NHC(CH3)3
OH
O
O
O
O
H3C
H3C
NHC(CH3)3
OH
HO
HO
COOH
CH3
p-Toluic Acid
2
Esterase
Bitolterol
Colterol
Blood-brain barrier (BBB)Blood-brain barrier (BBB) is one of important is one of important membrane often targeted for drug delivery. membrane often targeted for drug delivery.
It is unique lipid-like protective barrier that prevents It is unique lipid-like protective barrier that prevents hydrophilic compounds from entering the brain hydrophilic compounds from entering the brain unless they are actively transported.unless they are actively transported.
a The blood brain barrier contains active enzyme a The blood brain barrier contains active enzyme
systems to protect the CNS even further.systems to protect the CNS even further.
۩ Consequently, molecular size and lipophilicity are Consequently, molecular size and lipophilicity are
often necessary, not sufficient, criteria for gaining often necessary, not sufficient, criteria for gaining
entry into the brain.entry into the brain.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
✵Bodor and co-workers have devised a Bodor and co-workers have devised a reversible redox reversible redox drug delivery system (RRDDS)drug delivery system (RRDDS) for getting drugs into the for getting drugs into the
CNS and then, once in, preventing their effluxCNS and then, once in, preventing their efflux..
The approach is based on the attachment of a hydrophilic The approach is based on the attachment of a hydrophilic drug to a lipophilic carrier (drug to a lipophilic carrier (a dihydropyridinea dihydropyridine) thereby ) thereby
making prodrug that actively transported into the brainmaking prodrug that actively transported into the brain..
N
H H
CH3
N
H H
CH3
Prodrug residueBlood-brain barrier
O
XR
O
XR
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
Once inside the brain, the lipophilic carrier Once inside the brain, the lipophilic carrier is converted enzymatically to a highly is converted enzymatically to a highly hydrophilic species (positively charged), hydrophilic species (positively charged), which is then enzymatically hydrolyzed which is then enzymatically hydrolyzed back to the drug and N-methylnicotinic back to the drug and N-methylnicotinic acid, which is eliminated from the brain. acid, which is eliminated from the brain.
♫ The The oxidationoxidation of the dihydropyridine to of the dihydropyridine to
the pyridinium ion (half-life generally 20-the pyridinium ion (half-life generally 20-
50 min) prevents the drug from escaping 50 min) prevents the drug from escaping
out of the brain because it becomes out of the brain because it becomes
charged.charged.
♫ This drives the equilibrium of the This drives the equilibrium of the
lipophilic precursor throughout all of the lipophilic precursor throughout all of the
tissues of the body to favor the brain.tissues of the body to favor the brain.
N
H H
CH3
N
CH3
Enzymatic oxidation
O
XR
X
OR
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
N
H H
CH3
N
H H
CH3
Prodrug residueBlood-brain barrier
N
CH3
Drug release
by a suitable process
HX R+
N
CH3
HOOC
Enzymatic oxidation
Drug
O
XR
O
XR
X
OR
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
♫The functional group on the drug should be an amino, The functional group on the drug should be an amino,
hydroxyl, or carboxyl group.hydroxyl, or carboxyl group.
♫When it is a carboxylic acid, the linkage is an When it is a carboxylic acid, the linkage is an
acyloxymethyl ester, which decomposes as in acyloxymethyl ester, which decomposes as in
pivampicillin.pivampicillin.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
♫Any oxidation occurring outside of the brain produces a Any oxidation occurring outside of the brain produces a
hydrophilic species that can be rapidly eliminated from hydrophilic species that can be rapidly eliminated from
the body.the body.
♫The released oxidized carrier is relatively nontoxic and The released oxidized carrier is relatively nontoxic and
easily eliminated from the brain.easily eliminated from the brain.
♫Although this is a carrier-linked prodrug, it requires Although this is a carrier-linked prodrug, it requires
enzymatic oxidation to target the drug to the brain.enzymatic oxidation to target the drug to the brain.
♫The oxidation reaction is a bioprecursor reaction. The oxidation reaction is a bioprecursor reaction.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
The brain delivery of The brain delivery of -lactam antibiotics-lactam antibiotics for the possible for the possible
treatment of bacterial meningitis.treatment of bacterial meningitis.
Since the Since the -lactam antibiotics are hydrophilic, they -lactam antibiotics are hydrophilic, they
enter the brain very slowly, but they are actively enter the brain very slowly, but they are actively
transported back into the blood.transported back into the blood.
Therefore, they are not as effective in the treatment of Therefore, they are not as effective in the treatment of
brain infections as elsewhere.brain infections as elsewhere.
Bodor and co-workers prepared a variety of penicillin Bodor and co-workers prepared a variety of penicillin
prodrugs attached to the dihydropyridine carrier prodrugs attached to the dihydropyridine carrier
through various linkers and showed that through various linkers and showed that -lactam -lactam
antibiotics could be delivered in high concentrations antibiotics could be delivered in high concentrations
into the brain. into the brain.
RRDDSRRDDS
N
O
HN
O
NH2
S
O OO
O
N
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
Increasing the brain concentration of the inhibitory neurotransmitter Increasing the brain concentration of the inhibitory neurotransmitter -aminobutyric acid-aminobutyric acid
(GABA) results in anticonvulsant activity.(GABA) results in anticonvulsant activity.
GABA is too polar to cross the blood-brain barrier, so it is not an effective GABA is too polar to cross the blood-brain barrier, so it is not an effective
anticonvulsant drug.anticonvulsant drug.
To increase the lipophilicity of GABA, a series of GABT and To increase the lipophilicity of GABA, a series of GABT and -aminobutyric Schiff bases -aminobutyric Schiff bases
were synthesized.were synthesized.
ProgabideProgabide emerged as an effective lipophilic analog of GABA that crosses the blood- emerged as an effective lipophilic analog of GABA that crosses the blood-
brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.
N
NH2
O
F
Cl
OH
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
3.3.The synthesis of a glyceryl lipid (R=linolenoyl) The synthesis of a glyceryl lipid (R=linolenoyl)
containing onecontaining one GABA molecule and one vigabatrin GABA molecule and one vigabatrin
molecule, a mechanism-based inactivator of GABA molecule, a mechanism-based inactivator of GABA
aminotransferase and anticonvulsant drug.aminotransferase and anticonvulsant drug.
This compound inactivates GABA aminotransferase This compound inactivates GABA aminotransferase in in
vitro vitro only if brain esterases are added to cleave the only if brain esterases are added to cleave the
vigabatrin from the glyceryl lipid.vigabatrin from the glyceryl lipid.
It also is 300 times more potent than vigabatrin, It also is 300 times more potent than vigabatrin, in in
vivovivo, presumably because of its increased ability to , presumably because of its increased ability to
enter the brain. enter the brain.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
D.D.the application prodrugs to site-specific drug delivery the application prodrugs to site-specific drug delivery
-Glutamyl dopa-Glutamyl dopa is an example of a site-specific is an example of a site-specific
prodrug of levodopa (L-dopa).prodrug of levodopa (L-dopa).
L-dopa is precursor of the neurotransmitter dopamine, L-dopa is precursor of the neurotransmitter dopamine,
which plays an important role in the CNS and also which plays an important role in the CNS and also
exerts receptor-mediated vasodilation in the kidney.exerts receptor-mediated vasodilation in the kidney.
Prodrugs for (increased) Site Prodrugs for (increased) Site SpecificitySpecificity
Intraperitoneal injection of Intraperitoneal injection of -glutamyl -glutamyl
dopa into mice led to the selective dopa into mice led to the selective
generation of dopamine in the kidney generation of dopamine in the kidney
as a consequence of the sequential as a consequence of the sequential
actions of actions of -glutamyl transpeptidase-glutamyl transpeptidase
and and L-aromatic amino acid L-aromatic amino acid
decarboxylasedecarboxylase, two enzymes that are , two enzymes that are
highly concentrated in the kidney.highly concentrated in the kidney.
The concentration of dopamine in the The concentration of dopamine in the
kidney after kidney after --glutamyl dopa glutamyl dopa
administration was five times higher administration was five times higher
than that after administration of an than that after administration of an
equivalent dose of L-dopa.equivalent dose of L-dopa.
NH2
CH
CH2C
NH
O CH2
C
OH
O
OHO
HO
HO
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
► This does occur in a very selective This does occur in a very selective
manner, suggesting that some N-manner, suggesting that some N-
acyl-acyl--glutamylsulfamethoxazole -glutamylsulfamethoxazole
derivatives may be useful as derivatives may be useful as
specific renal antibacterial agents specific renal antibacterial agents
and and -glutamyllevodopa or -glutamyllevodopa or --
glutamyldopamine as specific renal glutamyldopamine as specific renal
vasodilators.vasodilators.
NH
S
NH
O O
N
O
O
R
R =
OH
O
R'HN
R' = Acetyl, Butyl
N- Acetyl-L--glutamyl-sulfamethoxazole
Acetylase
Acetate + L--glutamyl-sulfamethoxazole
H2O -glutamyl transpeptidase
Sulfamethoxazole + Glutamic acid
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
E.E.Design a prodrug that requires activation by an Design a prodrug that requires activation by an
enzyme found predominantly at the desired site of enzyme found predominantly at the desired site of
action.action.
For example, For example, tumor cellstumor cells contain a higher contain a higher
concentration of phosphatases and amidase than do concentration of phosphatases and amidase than do
normal cells.normal cells.
Consequently, a prodrug of a cytotoxic agent could be Consequently, a prodrug of a cytotoxic agent could be
directed to tumor cells if either of these enzymes were directed to tumor cells if either of these enzymes were
important to the prodrug activation process.important to the prodrug activation process.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
Diethylstilbestrol diphosphate was originally designed Diethylstilbestrol diphosphate was originally designed
for site-specific delivery of diethylstilbestrol to prostatic for site-specific delivery of diethylstilbestrol to prostatic
carcinoma tissue.carcinoma tissue.
In general, though, this tumor-selective approach has In general, though, this tumor-selective approach has
not been very successful because the appropriate not been very successful because the appropriate
prodrugs are too polar to reach the enzyme site, the prodrugs are too polar to reach the enzyme site, the
relative enzymatic selectivity is insufficient, and the relative enzymatic selectivity is insufficient, and the
tumor cell perfusion rate is too poor. tumor cell perfusion rate is too poor.
designing prodrugs that are activated by enzymes found designing prodrugs that are activated by enzymes found mainly at the target sitemainly at the target site..This strategy has been used to design antitumour drugs This strategy has been used to design antitumour drugs because tumors contain higher proportions of because tumors contain higher proportions of phosphatasesphosphatases and and peptidasespeptidases than normal tissues. than normal tissues.For example, diethylstilboestrol diphosphate (Fosfestrol) For example, diethylstilboestrol diphosphate (Fosfestrol) has been used to deliver the oestrogen agonist has been used to deliver the oestrogen agonist diethylstilboestrol to prostatic carcinomas.diethylstilboestrol to prostatic carcinomas.
C C
C2H5
C2H5
O P OH
O
OH
OPHO
O
OH
Diethylstilboestrol diphosphate
C C
C2H5
C2H5
OHH2O
Diethylstilboestrol e
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
F.F.Certain glycosides of antiinflammatory steroids Certain glycosides of antiinflammatory steroids
designed to release the parent drugs in the colon.designed to release the parent drugs in the colon.
Since drug glycosides are bulkier and generally more Since drug glycosides are bulkier and generally more
hydrophilic than the corresponding drugs, their ability hydrophilic than the corresponding drugs, their ability
to cross the biological membranes is reduced.to cross the biological membranes is reduced.
Steroid glycosides are not cleaved by the enzymes of Steroid glycosides are not cleaved by the enzymes of
the small intestine.the small intestine.
In the colon, however, they are hydrolyzed by the In the colon, however, they are hydrolyzed by the
bacterial glycosidases, thus liberating the parent drugs bacterial glycosidases, thus liberating the parent drugs
in the large intestine. in the large intestine.
Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity
G.G.Two interesting examples are the prodrugs of N-Two interesting examples are the prodrugs of N-
acetylated sulfamethoxazole and of levodopa in which acetylated sulfamethoxazole and of levodopa in which
the carrier moieties are glutamic acid derivatives.the carrier moieties are glutamic acid derivatives.
►These prodrugs were designed on basis of the finding These prodrugs were designed on basis of the finding
of a particularly high concentration of an N-acylamino of a particularly high concentration of an N-acylamino
acid deacylase and acid deacylase and -glutamyl transpeptidase in the -glutamyl transpeptidase in the
kidneys and that these enzymes would hopefully kidneys and that these enzymes would hopefully
release the parent drugs in those organs.release the parent drugs in those organs.
Mutual OR Mutual OR Reciprocal prodrugsReciprocal prodrugs
Aspirin + ParacetamolAspirin + Paracetamol
The best aryl ester is The best aryl ester is
the the benorylatebenorylate, ,
which is a mutual which is a mutual
prodrug of Aspirin prodrug of Aspirin
and Paracetamol.and Paracetamol.
Advantages?Advantages?
O
O
O
O
O
NH
Sultamicillin (Self Protection)Sultamicillin (Self Protection)
N
S
O COOH
O O
Sulbactam(Beta-lactamase inhibitor)
N
S
O
HN
O
NH2
COOH
Ampicillin
N
S
O
C O
O
N
S
O
HN
O
NH2
C
O
O
O
O
Mutual Prodrug (Reciprocal Prodrugs)Mutual Prodrug (Reciprocal Prodrugs)
• Used for metastatic carcinoma of the prostate
• Promoiety also a drug!
• Prodrug is selectively taken up into estrogen receptor positive cells then urethane linkage is hydroylzed
• 17-alphaestradiol slow prostate cell growth
• Nornitrogen mustard is a weak alkylating agent
Actual alkylating species
CH3OH
HO
NHCl
Cl
NH+Cl-
ClNornitrogen mustard
Aziridine
Sodium phosphateandCarbon dioxide
CH3OPO3Na2
ON
OCl
Cl Estermustine Sodium PhosphateEmcyt® - Pharmacia & Upjohn
Famciclovir is a prodrug of penciclovir which is itself a Famciclovir is a prodrug of penciclovir which is itself a prodrugprodrug
Penciclovir is poorly absorbed from the gut owing to its Penciclovir is poorly absorbed from the gut owing to its polaritypolarity . .
Famciclovir is less polar and is absorbed more easily. It is Famciclovir is less polar and is absorbed more easily. It is then metabolized, mainly in the liver, to form penciclovir then metabolized, mainly in the liver, to form penciclovir
which is phosphorylated in virally infected cellswhich is phosphorylated in virally infected cells..
N
NN
NAcO
OAc
NH2 N
NN
NHO
OH
NH2
Liver
Famciclovir Penciclovir
N
NN
NO
OH
NH2
Viral thymidinekinase
PN
NN
NO
OH
NH2PPP Cell
kinase
FamciclovirFamciclovir
N
N
N
N
O
H2N
O
Famciclovir
O
O
N
N
N
N
HO
H2N
HO
N
N
N
N
O
O
H2N
H
HO
P
PP
N
N
N
N
HO
O
H2N
H
HO
Penciclovir
BioprecursorsBioprecursors
Bioprecursor ProdrugsBioprecursor Prodrugs Bioprecursor” prodrugBioprecursor” prodrug
A compound that is metabolized into an active drug, usually A compound that is metabolized into an active drug, usually by Phase I reactions; eg acetanilideby Phase I reactions; eg acetanilide
Do Do NOTNOT contain a carrier or promoiety contain a carrier or promoiety– Contain latent functionalityContain latent functionality
– Metabolically or chemically transformed into an active Metabolically or chemically transformed into an active drugdrug
– Types of activation at are predictableTypes of activation at are predictableOxidative (most common method)Oxidative (most common method)
ReductiveReductivePhosphorylation (antiviral agents)Phosphorylation (antiviral agents)
– Non-steroidal antiinflammatory
Use: Arthritis
Oxidation Example – Oxidation Example – Nabumetone – Nabumetone – RelafenRelafen®® – Smith Kline Beecham – Smith Kline Beecham
CH3
O
CH3O
OH
CH3OO
Series of oxidative
decarboxylation
Active form of the drugthat inhibits Prostaglandinbiosynthesis bycyclooxygenase
Reduction exampleReduction example - Mitomycin C - Mutamycin - Mitomycin C - Mutamycin®® - Bristol - Bristol Myers Myers Adenocarcinoma of the stomach and pancreasAdenocarcinoma of the stomach and pancreas
Bioprecursor ProdrugsBioprecursor Prodrugs
N
O
O
H2N
CH3
O
H2NO
NHOMe
H
A quinone -electron withdrawing
-H+
-CO2
-NH3
Electrophile
DNA
H2N
CH3NHN
OH
OH
N
H2N
CH3
O
H2NO
NH
H
+
H2N
CH3
O
H2NO
NHN
OH
OH
H+
-OCH3
N
OH
OH
H2N
CH3
O
H2NO
NHOMe
H
A hydroquinone -electron donating
Reduction
DNA
H2N
CH3NHN
OH
OH+
Further alkylation
Examples - BioprecursorExamples - Bioprecursor
Minoxidil is an antihypertensive that is also used as to prevent Minoxidil is an antihypertensive that is also used as to prevent hair loss (Rogaine/Regaine)hair loss (Rogaine/Regaine)
The active constituent is a Phase II metabolite, minoxidil sulfateThe active constituent is a Phase II metabolite, minoxidil sulfate
N
N NH2H2N
O
N
N NH2H2N
OSO3
minoxidil minoxidil sulfate
Phase IImetabolism
Pilocarpine BioprecursesPilocarpine Bioprecurses
N
NO
ORHO
N
NO
ORO
N
N
O
O
Invivo
R = Ethyl, Butyl, Benzyl, OR others
b) Sulfoxide Reductionb) Sulfoxide Reduction
The antiarthritis drug The antiarthritis drug sulindacsulindac is an indene isoster of is an indene isoster of indomethacin, which originally was designed as a serotonin indomethacin, which originally was designed as a serotonin analog.analog.
Sulindac is a prodrug for Sulindac is a prodrug for Sulindac sulfideSulindac sulfide, the metabolitc , the metabolitc reductive product reductive product
H
CH3
CH2COOH
R
F
R = S CH3 S CH3 S CH3
O
O
O
N-OxidationN-Oxidation
N-Oxidation prodrug activation reactionN-Oxidation prodrug activation reaction
is the reversible redox drug delivery is the reversible redox drug delivery
strategy for getting drugs into the brain.strategy for getting drugs into the brain.
In case of N-Methylpyridinium-2-In case of N-Methylpyridinium-2-
carbaldoxime chloride (2-PAM) is used as carbaldoxime chloride (2-PAM) is used as
an antidote to poisoning with an antidote to poisoning with
cholinesterase inhibitors.cholinesterase inhibitors.
Because of its charge and hydrophilicity Because of its charge and hydrophilicity
it does not penetrate the blood-brain it does not penetrate the blood-brain
barrier. barrier.
N
CH3
CH
NOH
2-PAM
.Cl
N
CH3
CH
NOH
2-PAM
.Cl
N
CH3
CH
NOH
Pro-2-PAM
Pro-2-PAM , the reduced
dihydropyridine form of 2-PAM,
readily enters she central
nervous system.
There it is oxidized to form 2-
PAM, which remains trapped in
the CNS since its charge reduces
its rate of transfer from the brain
back into the blood.
Pro-2-PAM
Phosphorylation examplePhosphorylation example– – Bioprecursor ProdrugsBioprecursor Prodrugs
O
HNO
O
I
OH
OP-OO
O-
Viral Thymidine
KinaseO
HNO
O
I
OH
HO
Iodoxuridine - Herplex®
Allergan - lipid soluble!Opthalmic product forHerpes simplex keratitisHigher affininty for viralkinases than mammaliankinases but some toxicity O
HNO
O
I
OH
OPOO
O-POP-OO
O-
O
O-
TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporatedinto DNA affording incorrect base pairing and template activity
ATP
Not lipid soluble
We have already seen 2 examples of this:We have already seen 2 examples of this:– Sulfasalazine – an azo compoundSulfasalazine – an azo compound– Methenamine – An urinary antibacterial agentMethenamine – An urinary antibacterial agent
RequirementsRequirements– Prodrug reach the site of action in high Prodrug reach the site of action in high
concentrationsconcentrations– Knowledge of high metabolism at siteKnowledge of high metabolism at site– Other factors Other factors
Extent of organ or site perfusionExtent of organ or site perfusion Information on the rate of prodrug conversion to the active form Information on the rate of prodrug conversion to the active form at both target and non-target sitesat both target and non-target sites Rate of input/output of prodrug from the target siteRate of input/output of prodrug from the target site
Limit side effects and increase effectivenessLimit side effects and increase effectiveness
Chemical Delivery SystemsChemical Delivery Systems