Prodrugs II

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Prodrugs II

• Prepared By
• Professor Mohamed Ahmed Moustafa
• Professor of Medicinal Chemistry

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Prodrugs for (increased) Site Specificity
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DRUG TARGETING
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Prodrugs for Site Specificity

• Site-specific drug delivery attempts to obtain
  very precise and direct effects at the site of
  action without subjecting the rest of the body
  to significant levels of the active agent.

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.
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Prodrugs for (increased) Site Specificity

• To increase the site specificity of certain
  drugs, the following means of preparing prodrugs
  are used
• Increase or reduction in volume
• Alteration of hydrophilicity or solubility
• Introduction or removal of cationic or anionic
  moieties
• Change of pKa
• Incorporation of hydrocarbon or other suitable
  stable or labile moieties, and carriers that
  transport the compound to specific organs or
  tissues and make it to accumulate selectively
  there, where it is bioactivated.

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Prodrugs for GIT

• A nice objective of using prodrugs is to restrict
  the drug action to the upper part of the GIT
• If we want to target drugs against an infection
  of the GIT, then we want to prevent the drugs
  being absorbed into the blood supply.
• How??
• Retardation of the drug absorption, as in case of
  sulfathiazole

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Targetting infections of the GIT

• How would you decrease the absorption of this
  drug?
• This can easily be done by using a fully ionized
  molecule which is incapable of crossing cell
  membranes.
• The incorporation of strongly hydrophilic
  moieties to the sulfonamides prevents their
  transport to the bloodstream.
• They are incapable of crossing the gut wall and
  are therefore directed efficiently against the GI
  infection.

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Prodrugs for (increased) Site Specificity
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.

• used as intestinal antibacterial agent.

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Prodrugs for (increased) Site Specificity

• Bitolterol, a prodrug of the ?-blocker colterol.
• The toluate groups in both aromatic hydroxyls
  prevent the methylation of one of the groups by
  the enzyme COMT, until these groups are removed
  by hydrolysis by the esterases present in the
  tissues and in the blood.
• Bitolterol accumulates selectively in the lungs,
  where it partially and immediately releases
  colterol, which stimulate ?-adrenergic receptors
  and then adenylatic cyclase, with the consequent
  relaxation of the bronchial smooth muscles.

Bitolterol
Esterase
Colterol
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Site Specificity Brain

• Blood-brain barrier (BBB) is one of important
  membrane often targeted for drug delivery.
• It is unique lipid-like protective barrier that
  prevents hydrophilic compounds from entering the
  brain unless they are actively transported.
• a The blood brain barrier contains active enzyme
  systems to protect the CNS even further.
• Consequently, molecular size and lipophilicity
  are often necessary, not sufficient, criteria for
  gaining entry into the brain.

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Prodrugs for (increased) Site Specificity

• Bodor and co-workers have devised a reversible
  redox drug delivery system (RRDDS) for getting
  drugs into the CNS and then, once in, preventing
  their efflux.
• The approach is based on the attachment of a
  hydrophilic drug to a lipophilic carrier (a
  dihydropyridine) thereby making prodrug that
  actively transported into the brain.

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Prodrugs for (increased) Site Specificity

• Once inside the brain, the lipophilic carrier is
  converted enzymatically to a highly hydrophilic
  species (positively charged), which is then
  enzymatically hydrolyzed back to the drug and
  N-methylnicotinic acid, which is eliminated from
  the brain.
• The oxidation of the dihydropyridine to the
  pyridinium ion (half-life generally 20-50 min)
  prevents the drug from escaping out of the brain
  because it becomes charged.
• This drives the equilibrium of the lipophilic
  precursor throughout all of the tissues of the
  body to favor the brain.

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Prodrugs for (increased) Site Specificity
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Prodrugs for (increased) Site Specificity

• The functional group on the drug should be an
  amino, hydroxyl, or carboxyl group.
• When it is a carboxylic acid, the linkage is an
  acyloxymethyl ester, which decomposes as in
  pivampicillin.

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Prodrugs for (increased) Site Specificity

• Any oxidation occurring outside of the brain
  produces a hydrophilic species that can be
  rapidly eliminated from the body.
• The released oxidized carrier is relatively
  nontoxic and easily eliminated from the brain.
• Although this is a carrier-linked prodrug, it
  requires enzymatic oxidation to target the drug
  to the brain.
• The oxidation reaction is a bioprecursor
  reaction.

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Prodrugs for (increased) Site Specificity

• The brain delivery of ?-lactam antibiotics for
  the possible treatment of bacterial meningitis.
• Since the ?-lactam antibiotics are hydrophilic,
  they enter the brain very slowly, but they are
  actively transported back into the blood.
• Therefore, they are not as effective in the
  treatment of brain infections as elsewhere.
• Bodor and co-workers prepared a variety of
  penicillin prodrugs attached to the
  dihydropyridine carrier through various linkers
  and showed that ?-lactam antibiotics could be
  delivered in high concentrations into the brain.

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RRDDS
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Prodrugs for (increased) Site Specificity

• Increasing the brain concentration of the
  inhibitory neurotransmitter ?-aminobutyric acid
  (GABA) results in anticonvulsant activity.
• GABA is too polar to cross the blood-brain
  barrier, so it is not an effective anticonvulsant
  drug.
• To increase the lipophilicity of GABA, a series
  of GABT and ?-aminobutyric Schiff bases were
  synthesized.
• Progabide emerged as an effective lipophilic
  analog of GABA that crosses the blood-brain
  barrier, releases GABA inside the brain, and
  shows anticonvulsant activity.

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Prodrugs for (increased) Site Specificity

• The synthesis of a glyceryl lipid (Rlinolenoyl)
  containing one GABA molecule and one vigabatrin
  molecule, a mechanism-based inactivator of GABA
  aminotransferase and anticonvulsant drug.
• This compound inactivates GABA aminotransferase
  in vitro only if brain esterases are added to
  cleave the vigabatrin from the glyceryl lipid.
• It also is 300 times more potent than vigabatrin,
  in vivo, presumably because of its increased
  ability to enter the brain.

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Prodrugs for (increased) Site Specificity

• the application prodrugs to site-specific drug
  delivery ?-Glutamyl dopa is an example of a
  site-specific prodrug of levodopa (L-dopa).
• L-dopa is precursor of the neurotransmitter
  dopamine, which plays an important role in the
  CNS and also exerts receptor-mediated
  vasodilation in the kidney.

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Prodrugs for (increased) Site Specificity

• Intraperitoneal injection of ?-glutamyl dopa into
  mice led to the selective generation of dopamine
  in the kidney as a consequence of the sequential
  actions of ?-glutamyl transpeptidase and
  L-aromatic amino acid decarboxylase, two enzymes
  that are highly concentrated in the kidney.
• The concentration of dopamine in the kidney after
  ?-glutamyl dopa administration was five times
  higher than that after administration of an
  equivalent dose of L-dopa.

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Prodrugs for (increased) Site Specificity

• This does occur in a very selective manner,
  suggesting that some N-acyl-?-glutamylsulfamethoxa
  zole derivatives may be useful as specific renal
  antibacterial agents and ?-glutamyllevodopa or
  ?-glutamyldopamine as specific renal vasodilators.

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Prodrugs for (increased) Site Specificity

• Design a prodrug that requires activation by an
  enzyme found predominantly at the desired site of
  action.
• For example, tumor cells contain a higher
  concentration of phosphatases and amidase than do
  normal cells.
• Consequently, a prodrug of a cytotoxic agent
  could be directed to tumor cells if either of
  these enzymes were important to the prodrug
  activation process.

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Prodrugs for (increased) Site Specificity

• Diethylstilbestrol diphosphate was originally
  designed for site-specific delivery of
  diethylstilbestrol to prostatic carcinoma tissue.
• In general, though, this tumor-selective approach
  has not been very successful because the
  appropriate prodrugs are too polar to reach the
  enzyme site, the relative enzymatic selectivity
  is insufficient, and the tumor cell perfusion
  rate is too poor.

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Site Specificity

• designing prodrugs that are activated by enzymes
  found mainly at the target site.
• This strategy has been used to design antitumour
  drugs because tumors contain higher proportions
  of phosphatases and peptidases than normal
  tissues.
• For example, diethylstilboestrol diphosphate
  (Fosfestrol) has been used to deliver the
  oestrogen agonist diethylstilboestrol to
  prostatic carcinomas.

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Prodrugs for (increased) Site Specificity

• Certain glycosides of antiinflammatory steroids
  designed to release the parent drugs in the
  colon.
• Since drug glycosides are bulkier and generally
  more hydrophilic than the corresponding drugs,
  their ability to cross the biological membranes
  is reduced.
• Steroid glycosides are not cleaved by the enzymes
  of the small intestine.
• In the colon, however, they are hydrolyzed by the
  bacterial glycosidases, thus liberating the
  parent drugs in the large intestine.

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Prodrugs for (increased) Site Specificity

• Two interesting examples are the prodrugs of
  N-acetylated sulfamethoxazole and of levodopa in
  which the carrier moieties are glutamic acid
  derivatives.
• These prodrugs were designed on basis of the
  finding of a particularly high concentration of
  an N-acylamino acid deacylase and ?-glutamyl
  transpeptidase in the kidneys and that these
  enzymes would hopefully release the parent drugs
  in those organs.

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• Mutual OR Reciprocal prodrugs

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Aspirin Paracetamol

• The best aryl ester is the benorylate, which is a
  mutual prodrug of Aspirin and Paracetamol.
• Advantages?

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Sultamicillin (Self Protection)
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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

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Prodrugs of prodrugs

• Famciclovir is a prodrug of penciclovir which is
  itself a prodrug
• Penciclovir is poorly absorbed from the gut owing
  to its polarity.
• Famciclovir is less polar and is absorbed more
  easily. It is then metabolized, mainly in the
  liver, to form penciclovir which is
  phosphorylated in virally infected cells.

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Famciclovir
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• Bioprecursors

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Bioprecursor Prodrugs

• Bioprecursor prodrug
• A compound that is metabolized into an active
  drug, usually by Phase I reactions eg
  acetanilide
• Do NOT contain a carrier or promoiety
• Contain latent functionality
• Metabolically or chemically transformed into an
  active drug
• Types of activation at are predictable
• Oxidative (most common method)
• Reductive
• Phosphorylation (antiviral agents)

Non-steroidal antiinflammatory Use Arthritis
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Oxidation Example Nabumetone Relafen Smith
Kline Beecham
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Bioprecursor Prodrugs

• Reduction example - Mitomycin C - Mutamycin -
  Bristol Myers Adenocarcinoma of the stomach and
  pancreas

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Examples - Bioprecursor

• Minoxidil is an antihypertensive that is also
  used as to prevent hair loss (Rogaine/Regaine)
• The active constituent is a Phase II metabolite,
  minoxidil sulfate

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Pilocarpine Bioprecurses
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b) Sulfoxide Reduction

• The antiarthritis drug sulindac is an indene
  isoster of indomethacin, which originally was
  designed as a serotonin analog.
• Sulindac is a prodrug for Sulindac sulfide, the
  metabolitc reductive product

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N-Oxidation

• N-Oxidation prodrug activation reaction is the
  reversible redox drug delivery strategy for
  getting drugs into the brain.
• In case of N-Methylpyridinium-2-carbaldoxime
  chloride (2-PAM) is used as an antidote to
  poisoning with cholinesterase inhibitors.
• Because of its charge and hydrophilicity it does
  not penetrate the blood-brain barrier.

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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.
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Bioprecursor Prodrugs

• Phosphorylation example

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Chemical Delivery Systems

• We have already seen 2 examples of this
• Sulfasalazine an azo compound
• Methenamine An urinary antibacterial agent
• Requirements
• Prodrug reach the site of action in high
  concentrations
• Knowledge of high metabolism at site
• Other factors
• Extent of organ or site perfusion
• Information on the rate of prodrug conversion to
  the active form at both target and non-target
  sites
• Rate of input/output of prodrug from the target
  site
• Limit side effects and increase effectiveness

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Thank You