THE ORGANIC CHEMISTRY OF DRUG
DESIGN AND DRUG ACTION
Chapter 9
Prodrugs and Drug Delivery Systems
PRODRUGS AND DRUG DELIVERY SYSTEMS
Prodrug - a pharmacologically inactive compound that is
converted to an active drug by a metabolic
biotransformation
Ideally, conversion occurs as soon as the desired goal for
designing the prodrug is achieved.
Prodrugs and soft drugs are opposite:
• a prodrug is inactive - requires metabolism to give active form
• a soft drug is active - uses metabolism to promote excretion
A pro-soft drug would require metabolism to convert it to a soft drug
UTILITY OF PRODRUGS
1. Aqueous Solubility - to increase water
solubility so it can be injected in a small volume
2. Absorption and Distribution - to increase lipid
solubility to penetrate membranes for better
absorption and ability to reach site of action
3. Site Specificity - to target a particular organ or
tissue if a high concentration of certain enzymes is
at a particular site or append something that directs
the drug to a particular site
Utility of Prodrugs (cont’d)
4. Instability - to prevent rapid metabolism; avoid
first-pass effect
5. Prolonged Release - to attain a slow, steady
release of the drug
6. Toxicity - to make less toxic until it reaches the
site of action
7. Poor Patient Acceptability - to remove an
unpleasant taste or odor; gastric irritation
8. Formulation Problems - to convert a drug that
is a gas or volatile liquid into a solid
TYPES OF PRODRUGS
DRUG LATENTIATION - RATIONAL PRODRUG DESIGN
I. Carrier-linked prodrug
A compound that contains an active drug linked to a carrier group
that is removed enzymatically
A. bipartate - comprised of one carrier attached to drug
B. tripartate - carrier connected to a linker that is connected to
drug
C. mutual - two, usually synergistic, drugs attached to each other
II. Bioprecursor prodrug
A compound metabolized by molecular modification into a new
compound, which is a drug or is metabolized further to a drug - not
just simple cleavage of a group from the prodrug
PROTECTING GROUP ANALOGY FOR
THE CONCEPT OF PRODRUGS
A.
RCO2H
B.
RCH=CH2
EtOH
HCl

reactio n
on R
RCO2 Et
reactio n
on R
R'CH=CH2
R'CO2Et
1. O3
2. H2O2
H3O+

R'CO2H
R'CO2H
analogous to
carrier-linked
analogous to
bioprecursor
SCHEME 9.1 Protecting group analogy for a prodrug
Keep in mind that a prodrug whose design is based on rat
metabolism may not be effective in humans.
MECHANISMS OF PRODRUG
ACTIVATION
CARRIER-LINKED PRODRUGS
Most common activation reaction is hydrolysis.
IDEAL DRUG CARRIERS
1. Protect the drug until it reaches the site of action
2. Localize the drug at the site of action
3. Allow for release of drug
4. Minimize host toxicity
5. Are biodegradable, inert, and nonimmunogenic
6. Are easily prepared and inexpensive
7. Are stable in the dosage form
CARRIER LINKAGES FOR VARIOUS
FUNCTIONAL GROUPS
ALCOHOLS, CARBOXYLIC ACIDS, AND RELATED
GROUPS
Most common prodrug form is an ester
• esterases are ubiquitous
• can prepare esters with any degree of hydrophilicity or
lipophilicity
• ester stability can be controlled by appropriate
electronic and steric manipulations
PRODRUGS FOR
ALCOHOL-CONTAINING
DRUGS
Ester analogs as
prodrugs can affect
lipophilicity or
hydrophilicity
To accelerate the hydrolysis rate:
• attach an electron-withdrawing group if a base
hydrolysis mechanism is important
• attach an electron-donating group if an acid
hydrolysis mechanism is important
To slow down the hydrolysis rate:
• make sterically-hindered esters
• make long-chain fatty acid esters
HYDROLYSIS OF AMINO ACID ESTERS OF
BRIVANIB
ANOTHER APPROACH TO ACCELERATE
HYDROLYSIS
INTRAMOLECULAR HYDROLYSIS OF SUCCINATE ESTERS
SCHEME 9.2 Intramolecular catalysis of succinate esters
Enolic hydroxyl groups can be esterified as well.
antirheumatic agent
CARBOXYLIC ACID-CONTAINING
GROUPS
ESTERIFY AS WITH ALCOHOLS
MAINTAINING WATER SOLUBILITY OF
CARBOXYLATE PRODRUGS
Can vary pKa by appropriate choice of R and R
PRODRUGS FOR PHOSPHATE- OR
PHOSPHONATE-CONTAINING DRUGS
AMINE PRODRUGS
Amides are commonly not used because of stability
Activated amides (low basicity amines or amino acids)
are effective
pKa of amines can be lowered by 3 units by conversion
to N-Mannich bases (X = CH2NHCOAr)
N-Mannich base (R = CH2NHCOPh) has a log D7.4
two units greater than the parent compound.
Another approach to lower pKa of amines and
make more lipophilic.
Imine (Schiff base) prodrug
hydrolyze imine and
amide to GABA
inside brain
anticonvulsant
ACYLATION OF AN AMIDINE TO MAKE A
PRODRUG
Thrombin inhibitor
anticoagulant
A REDUCTIVE CARRIER-LINKED
PRODRUG APPROACH
SCHEME 9.3 Bioreductively activated carrier-linked prodrug
PRODRUGS OF SULFONAMIDES
A water soluble prodrug of the anti-inflammatory
drug valdecoxib (9.13) has been made (9.14).
PRODRUG ANALOGS OF CARBONYL
COMPOUNDS
imines
oximes
ketals
Acetals or ketals can be made for rapid hydrolysis in the
acidic medium of the GI tract.
EXAMPLES OF CARRIER-LINKED
BIPARTATE PRODRUGS
Prodrug Stability Properties
Choice of hydrolytic prodrug group: The group must be stable
enough in water for a shelf life of > 2 years (13 year half-life),
but must be hydrolyzed in vivo with a half-life < 10 minutes.
Therefore, in vivo/in vitro lability ratio about 106.
PRODRUG FOR INCREASED WATER
SOLUBILITY
O
R' = CCH2CH2CO2 Na
Prodrug forms
R' = PO3Na2
for aqueous injection or
opthalmic use
corticosteroid
poor water
solubility
To avoid formulation of etoposide with detergent,
PEG, and EtOH (used to increase water solubility),
it has been converted to the phosphate prodrug.
PRODRUGS OF BENZOCAINE WITH AMINO ACIDS
R = NH2-CH(R)-CO
PRODRUG FOR IMPROVED
ABSORPTION THROUGH SKIN
corticosteroids - inflammation,
allergic, pruritic skin conditions
Better absorption into cornea for the treatment of
glaucoma
The cornea has significant esterase activity
PRODRUG FOR SITE SPECIFICITY
Bowel sterilant
(administer rectally)
Prodrug R = Ac (administered orally)
Hydrolyzed in the intestines
PRODRUG FOR SITE SPECIFICITY
The blood-brain barrier prevents hydrophilic molecules
from entering the brain, unless actively transported. The
anticonvulsant drug vigabatrin (see Chapter 5) crosses
poorly. A glyceryl lipid (9.21, R = linolenoyl) containing
one GABA ester and one vigabatrin ester was 300 times
more potent in vivo than vigabatrin.
PHOSPHATE PRODRUG FOR LIVER ACTIVITY
SCHEME 9.4 Liver metabolism of drugs containing phosphate and
phosphonate moieties
ANTIVIRAL PRODRUGS
SITE SPECIFICITY
USING ENZYMES AT
THE SITE OF ACTION
Phosphatase should release the drug selectively in
tumor cells. This approach has not been successful
because the prodrugs are too polar, enzyme selectivity
is not sufficient, or tumor cell perfusion rate is poor.
ENZYME-PRODRUG THERAPIES
For selective activation of prodrugs in tumor cells
Two steps:
1. incorporate a prodrug-activating enzyme into a
target tumor cell
2. administer a nontoxic prodrug which is a
substrate for the exogenous enzyme incorporated
Criteria for Success with Enzyme-Prodrug Therapies
1. The prodrug-activating enzyme is either nonhuman or a
human protein expressed poorly
2. The prodrug-activating enzyme must have high catalytic
activity
3. The prodrug must be a good substrate for the incorporated
enzyme and not for other endogenous enzymes
4. The prodrug must be able to cross tumor cell membranes
5. The prodrug should have low cytotoxicity and the drug high
cytotoxicity
6. The activated drug should be highly diffusable to kill
neighboring nonexpressing cells (bystander killing effect)
7. The half-life of the active drug is long enough for bystander
killing effect but short enough to avoid leaking out of tumor
cells
ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY
(ADEPT)
An approach for site-specific delivery of cancer drugs.
Phase One: An antibody-enzyme conjugate is administered
which binds to the surface of the tumor cells. The antibody
used has been targeted for the particular tumor cell. The
enzyme chosen for the conjugate is one that will be used to
cleave the carrier group off of the prodrug administered in
the next phase.
Phase Two: After the antibody-enzyme has accumulated on
the tumor cell and the excess conjugate is cleared from the
blood and normal tissues, the prodrug is administered. The
enzyme conjugated with the antibody at the tumor cell
surface catalyzes the conversion of the prodrug to the drug
when it reaches the tumor cell.
ADEPT
Advantages:
1. Increased selectivity for targeted cell
2. Each enzyme molecule converts many prodrug
molecules
3. The released drug is at the site of action
4. Concentrates the drug at the site of action
5. Demonstrated to be effective at the clinical level
Disadvantages:
1. Immunogenicity and rejection of antibody-enzyme
conjugate
2. Complexity of the two-phase system and i.v.
administration
3. Potential for leakback of the active drug
An example is carboxypeptidase G2 or alkaline phosphatase
linked to an antibody to activate a nitrogen mustard prodrug.
SCHEME 9.5 Nitrogen mustard activation by carboxypeptidase G2
for use with ADEPT
Humanization of antibodies minimizes immunogenicity.
Note the prodrug-activating enzyme is a bacterial enzyme.
ANTIBODY-DIRECTED ABZYME PRODRUG
THERAPY (ADAPT)
Instead of using a prodrug-activating enzyme, a
humanized prodrug-activating catalytic antibody
(abzyme) can be used.
Ideally, the abzyme catalyzes a reaction not known to
occur in humans, so the only site where the prodrug
could be activated is at the tumor cell where the
abzyme is bound.
Antibody 38C2 catalyzes sequential retro-aldol and
retro-Michael reactions not catalyzed by any known
human enzyme.
Found to be long-lived in vivo, to activate prodrugs
selectively, and to kill colon and prostate cancer cells.
ABZYME 38C2 ACTIVATION OF A
DOXORUBICIN PRODRUG
SCHEME 9.6 Catalytic antibody 38C2 activation of a doxorubicin prodrug
by tandem retro-aldol/retro-Michael reactions for use with ADAPT
GENE-DIRECTED ENZYME PRODRUG
THERAPY (GDEPT)
ALSO KNOWN AS SUICIDE GENE THERAPY
A gene encoding the prodrug-activating enzyme is expressed
in target cancer cells under the control of tumor-selective
promoters or by viral transfection. These cells activate the
prodrug as in ADEPT.
SCHEME 9.7 Nitroreductase activation of a prodrug for use with GDEPT
PRODRUG FOR STABILITY
PROTECTION FROM FIRST-PASS EFFECT
Oral administration has lower bioavailability than
i.v. injection.
antihypertension
O
pr od ru g R' = CCH2 CH2COOH
plasma levels 8 times that with propranolol
PRODRUG FOR NALTREXONE
R = Anthranilyl or acetylsalicyl
PRODRUGS FOR SLOW AND PROLONGED
RELEASE
1. To reduce the number and frequency of doses
2. To eliminate night time administration
3. To minimize patient noncompliance
4. To eliminate peaks and valleys of fast release
(relieve strain on cells)
5. To reduce toxic levels
6. To reduce GI side effects
Long-chain fatty acid esters hydrolyze slowly
Intramuscular injection is used also
TIME-RELEASE ANTIPSYCHOTICS
Sedative/tranquilizer/antipsychotic
O
prod ru g R' = C(CH2)8CH3
slow release
inject i.m.
Antipsychotic activity for about 1 month
TIME-RELEASE ANTIPSYCHOTICS
Activity about 1
month
A TIME-RELEASE ANTI-INFLAMMATORY DRUG
t1/2 about 9 h
PRODRUGS TO MINIMIZE TOXICITY
Many of the prodrugs just discussed also have
lower toxicity.
For example, epinephrine (for glaucoma) has
ocular and systemic side effects not found in
dipivaloylepinephrine.
Esters are prodrugs of aspirin
PRODRUG TO INCREASE PATIENT
ACCEPTANCE
The antibacterial drug
clindamycin (9.39) is
bitter and not well
tolerated by children.
Clindamycin palmitate
is not bitter.
Either not soluble in saliva or does not bind to the
bitter taste receptor or both.
ANOTHER BITTER DRUG WITH A TASTELESS
PRODRUG
PRODRUG TO ELIMINATE
FORMULATION PROBLEMS
Formaldehyde is a gas with a pungent odor that is used as a
disinfectant. Too toxic for direct use.
It is a stable solid that decomposes in aqueous acid.
The pH of urine in the bladder is about 4.8, so methenamine
is used as a urinary tract antiseptic.
Has to be enteric coated to prevent hydrolysis in the stomach.
A PRODRUG FOR RELEASE OF ACETIC ACID
AREAS OF IMPROVEMENT FOR PRODRUGS
• site specificity
• protection of drug from biodegradation
• minimization of side effects
MACROMOLECULAR DRUG DELIVERY
To address these shortcomings, macromolecular
drug delivery systems have been developed.
A bipartate carrier-linked prodrug in which the drug is
attached to a macromolecule, such as a synthetic polymer,
protein, lectin, antibody, cell, etc.
Absorption/distribution depends on the physicochemical
properties of macromolecular carrier, not of the drug.
Therefore, attain better targeting.
Minimize interactions with other tissues or enzymes.
Fewer metabolic problems; increased therapeutic index.
DISADVANTAGES OF
MACROMOLECULAR DELIVERY
SYSTEMS
• Macromolecules may not be well absorbed
• Alternative means of administration may be
needed (injection)
• Immunogenicity problems
MACROMOLECULAR DRUG CARRIERS
Synthetic polymers
Aspirin linked to poly(vinyl alcohol) has about the
same potency as aspirin, but less toxic.
A PRODRUG FOR IBUPROFEN
9.44 shows a longer half life and
longer anti-inflammatory activity
STERIC HINDRANCE BY POLYMER
CARRIER
poly(methacrylate)
to enhance
water
solubility
testosterone
No androgenic effect
Polymer backbone may be sterically hindering the
release of the testosterone.
A spacer arm was added, and it was as effective
as testosterone.
to enhance
water
solubility
POLY(-AMINO ACID) CARRIERS
poly(L-glutamine)
spacer
norethindrone - contraceptive
Slow release over nine months in rats
POLY(-AMINO ACID) CARRIERS
Methotrexate attached to poly(L-lysine)
showed increased uptake and overcame
resistance
GENERAL SITE-SPECIFIC MACROMOLECULAR
DRUG DELIVERY SYSTEM
either hydrophilic
or hydrophobic
for site specificity
SITE-SPECIFIC DELIVERY OF A NITROGEN MUSTARD
poly(L-Glu)
spacer
arm
water-solubilizing
antibody from
rabbit antiserum
against mouse
lymphoma cells
All 5 mice tested were alive and tumor free after 60
days (all controls died).
Also, therapeutic index greatly enhanced (40 fold).
TUMOR CELL SELECTIVITY
Drug attached to albumin (R = albumin)
Tumor cells take up
proteins rapidly. Proteins
broken down inside cells,
releasing the drug.
Shown to inhibit growth
of Ectomelia virus in
mouse liver, whereas free
inhibitor did not.
antitumor
ANTIBODY-TARGETED CHEMOTHERAPY
calicheamicin, except as disulfide
instead of trisulfide
humanized
spacer
SCHEME 9.8 Antibody-targeted chemotherapy, a prodrug for calicheamicin
Withdrawn due to release of calicheamicin nonenzymatically.
Exhibits no immune response.
ANTIBODY-TARGETED CHEMOTHERAPY
FIGURE 9.1 (A) Brentuximab vedotin, the first antibody-drug conjugate with
a more stable linker; (B) Trastuzumab emtansine, the second antobody-drug
conjugate approved
TRIPARTATE DRUGS
(SELF-IMMOLATIVE PRODRUGS)
A bipartate prodrug may be ineffective because the
linkage is too labile or too stable.
In a tripartate prodrug, the carrier is not attached to
the drug; rather, to the linker.
Therefore, more flexibility in the types of functional
groups and linkages that can be used, and it moves
the cleavage site away from the carrier.
The linker-drug bond must cleave spontaneously
(i.e., be self-immolative) after the carrier-linker
bond is broken.
TRIPARTATE PRODRUGS
SCHEME 9.9 Tripartite prodrugs
TYPICAL APPROACH
SCHEME 9.10 Double prodrug concept
TRIPARTATE PRODRUGS OF AMPICILLIN
Poor oral absorption (40%)
Excess antibiotic may destroy
important intestinal bacteria
used in digestion and for
biosynthesis of cofactors.
Also, more rapid onset of
resistance.
antibacterial
Various esters made were too stable in humans (although
they were hydrolyzed in rodents) - thought the thiazolidine
ring sterically hindered the esterase.
TRIPARTATE PRODRUGS OF AMPICILLIN
SCHEME 9.11 Tripartite prodrugs of ampicillin
98-99% absorbed
Ampicillin is released in < 15 minutes
REVERSIBLE REDOX DRUG DELIVERY SYSTEM TO THE CNS
hydrolysis deactivated
hydrophilic
drug
electron-donating,
lipophilic carrier
hydrolysis
activated
electronwithdrawing;
hydrophilic
Passive diffusion of 8.47 into the brain; active transport of 8.49
out of the brain
SCHEME 9.12 Redox drug delivery
to cross the blood–brain
XH of the drug is NH2, OH, or COOH system
barrier
If oxidation occurs before it gets into the brain, it cannot cross the
blood-brain barrier.
When the drug is a carboxylic acid, a selfimmolative reaction also can be used.
SCHEME 9.13 Redox tripartite drug delivery system
EXAMPLE OF TRIPARTATE REDOX DRUG
DELIVERY
-Lactams are too hydrophilic to cross the blood-brain
barrier effectively.
SCHEME 9.14 Redox tripartite drug delivery of β-lactam antibiotics
High concentrations of -lactams delivered into brain.
ANOTHER TRIPARTATE PRODRUG FOR
DELIVERY OF ANTITUMOR DRUG
Permeases are bacterial transport proteins for uptake
of peptides.
SCHEME 9.15 Activation of peptidyl derivatives of 5-fluorouracil
Only L,L-dipeptides are active
ANOTHER TRIPARTATE PRODRUG FOR DELIVERY OF
AMINES
SCHEME 9.16 Tripartite macromolecular drug delivery system
This has been applied
to daunorubicin
MUTUAL PRODRUGS
A bipartate or tripartate prodrug in which the carrier is a
synergistic drug with the drug to which it is linked.
Antibacterial
ampicillin
-lactamase inactivator
penicillanic acid sulfone
Hydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone :
formaldehyde
IDEAL MUTUAL PRODRUGS
• Well absorbed
• Both components are released together
and quantitatively after absorption
• Maximal effect of the combination of the
two drugs occurs at 1:1 ratio
• Distribution/elimination of components
are similar
BIOPRECURSOR PRODRUGS
Carrier-linked prodrugs largely use hydrolytic
activation
Bioprecursor drugs mostly use oxidative or
reductive activation
The metabolically-activated alkylating agents
discussed in Chapter 6 are actually examples of
bioprecursor prodrugs.
PROTONATION ACTIVATION
DISCOVERY OF OMEPRAZOLE
Cimetidine and ranitidine (Chapter 3) reduce
gastric acid secretion by antagonizing the H2
histamine receptor.
Another way to lower gastric acid secretion is by
inhibition of the enzyme H+,K+-ATPase (also
called the proton pump), which exchanges
protons for potassium ions in parietal stomach
cells, thereby increasing stomach acidity.
LEAD DISCOVERY
Lead compound found in a random screen.
Liver toxicity observed thought to be because of
the thioamide group.
LEAD MODIFICATION
Related analogs made, and 9.72 had good antisecretory
activity.
Modification gave 9.73 with high activity.
The sulfoxide (9.74) was more potent, but it blocked
iodine uptake into the thyroid.
LEAD MODIFICATION (CONT’D)
Modification of 9.74 gave
9.75 having no iodine
blockage activity.
Picoprazole shown to be an
inhibitor of H+,K+-ATPase.
SAR of analogs indicated
electron-donating groups on
the pyridine ring were
favorable. Increased inhibition
of H+,K+-ATPase.
Best analog was omeprazole
(9.76).
The pKa of the pyridine ring of omeprazole is about 4, so it is not
protonated and able to cross the secretory canaliculus of the parietal
cell. The pH inside the cell is below 1, so this initiates the
protonation reaction below.
SCHEME 9.17 Mechanism of inactivation of H+,K+-ATPase by omeprazole
Formation of 9.77 leads to covalent attachment.
Omeprazole also inhibits isozymes of carbonic anhydrase, another
mechanism for lowering gastric acid secretion.
OTHER PROTON PUMP INHIBITORS
HYDROLYTIC ACTIVATION
Hydrolysis can be a mechanism for bioprecursor
prodrug activation, if the product requires additional
activation.
SCHEME 9.18 Conversion of leinamycin into a series of prodrugs
antitumor agent
prodrugs of leinamycin
Hydrolysis of these analogs gives an intermediate
that reacts further to the activated form.
increased stability
over leinamycin
SCHEME 9.19 Hydrolytic activation of leinamycin prodrugs
this was
synthesized
and gave
9.85 as well
as DNA
cleavage
ELIMINATION ACTIVATION
rheumatoid arthritis drug
potent inhibitor of
dihydroorotate
dehydrogenase
SCHEME 9.20 Activation of leflunomide to the active drug
Inhibition of dihydroorotate dehydrogenase blocks
pyrimidine biosynthesis in human T lymphocytes.
OXIDATIVE ACTIVATION
N-DEALKYLATION
SCHEME 9.21 Bioprecursor prodrugs for alprazolam and triazolam
O-DEALKYLATION
Analgesic activity of phenacetin is a result
of O-dealkylation to acetaminophen.
OXIDATIVE DEAMINATION
Neoplastic (cancer) cells have a high concentration of
phosphoramidases, so hundreds of phosphamide analogs of nitrogen
mustards were made for selective activation in these cells.
Cyclophosphamide was very
effective, but it required liver
homogenates (contains P450)
for activation. Therefore
oxidation is required, not
hydrolysis.
SCHEME 9.22 Cytochrome P450catalyzed activation of cyclophosphamide
isolated
N-OXIDATION
identified
advanced Hodgkin’s
disease
SCHEME 9.23 Cytochrome P450-catalyzed activation
of procarbazine
identified
N-OXIDATION
Pralidoxime chloride is an antidote for nerve
poisons.
It reacts with acetylcholinesterase that has been
inactivated by organophosphorus toxins.
To increase the permeability of pralidoxime into
the CNS, the pyridinium ring was reduced (9.103).
oxidation in brain
Similar to the reversible redox drug delivery strategy for getting drugs
into the brain by attaching them to a dihydronicotinic acid,
hydrophobic 9.103 crosses the blood-brain barrier; oxidation to 9.102
prevents efflux from brain.
MECHANISM OF
ACETYLCHOLINESTERASE
SCHEME 9.24 Acetylcholinesterase-catalyzed hydrolysis of acetylcholine
INACTIVATION OF ACETYLCHOLINESTERASE
BY DIISOPROPYL PHOSPHOROFLUORIDATE
affinity labeling agent
irreversible inhibition
SCHEME 9.25 Phosphorylation of acetylcholinesterase by diisopropyl phosphorofluoridate
Inactivation prevents degradation of the excitatory
neurotransmitter acetylcholine. Accumulation of
acetylcholine causes muscle cells in airways to contract
and secrete mucous, then muscles become paralyzed.
REACTIVATION OF INACTIVATED
ACETYLCHOLINESTERASE BY
PRALIDOXIME
SCHEME 9.26 Reactivation of phosphorylated acetylcholinesterase by pralidoxime chloride
Temporary inhibition of acetylcholinesterase
enhances cholinergic action on skeletal muscle.
covalent, but
reversible
inhibition
Used for the neuromuscular
disease myasthenia gravis
SCHEME 9.27 Carbamylation of acetylcholinesterase by neostigmine
Reversible (noncovalent) inhibitors of
acetylcholinesterase, such as donepezil and tacrine
are used for Alzheimer’s disease. Enhances
neurotransmission involved in memory.
S-OXIDATION
S-oxidation of clopidogrel
anticoagulant
SCHEME 9.28 S-Oxidation of clopidogrel, which initiates its inactivation of P2Y12
AROMATIC HYDROXYLATION
CYCLOHEXENONES AS PRODRUGS FOR
CATECHOLS
oxidation next to
sp2 carbonyl
aromatic hydroxylation
SCHEME 9.29 Cytochrome P450-catalyzed conversion of a
cyclohexenone to a catechol
ALKENE EPOXIDATION
active anticonvulsant agent
TRANSAMINATION
Stimulation of pyruvate dehydrogenase results in a
change of myocardial metabolism from fatty acid
to glucose utilization.
Glucose metabolism requires less O2 consumption.
Therefore, utilization of glucose metabolism would
be beneficial to patients with ischemic heart
disease (arterial blood flow blocked; less O2
available).
Arylglyoxylic acids (8.104) stimulate pyruvate
dehydrogenase, but have a short duration of action.
Oxfenicine (8.105, R = OH) is actively transported and is
transaminated (a PLP aminotransferase) in the heart to
8.104 (R = OH).
REDUCTIVE ACTIVATION
AZO REDUCTION
ulcerative colitis
For inflammatory
bowel disease
SCHEME 9.30 Reductive activation of sulfasalazine
Anaerobic cleavage
by bacteria in lower
bowel
Causes side effects
To prevent side effect by sulfapyridine a
macromolecular delivery system was developed.
poly(vinylamine)
Not absorbed or
metabolized in small
intestine.
CO 2Na
NH 2
OH
spacer
Released by reduction at the disease site.
Sulfapyridine is not released (still attached to polymer).
More potent than sulfasalazine.
AZIDO REDUCTION
antiviral drug
Vidarabine is rapidly deaminated by adenosine deaminase.
8.110, R = N3 is not a substrate for adenosine deaminase and
also can cross the blood-brain barrier for brain infections.
SULFOXIDE REDUCTION
anti-arthritis
Sulindac is inactive in vitro; the sulfide is active in
vitro and in vivo.
Sulindac is an indane isostere of indomethacin, which was designed
as a serotonin analog.
The 5-F replaced the 5-OMe group to increase analgesic properties.
The p-SOCH3 group replaced p-Cl to increase water solubility.
DISULFIDE REDUCTION
To increase the lipophilicity of thiamin for absorption into
the CNS.
nonenzymatic
poorly absorbed into CNS
SCHEME 9.31
Conversion of thiamin tetrahydrofurfuryl disulfide to thiamin
To diminish toxicity of
primaquine and target it for
cells with the malaria
parasite, a macromolecular
drug delivery system was
designed.
antimalarial, toxic
Intracellular thiol much higher
than in blood; selective
reduction inside the cell
primaquine
for
improved
uptake in liver
Therapeutic index of 9.128 is 12 times higher than 9.127 in mice.
NITRO REDUCTION
SCHEME 9.32 Reductive activation of ronidazole
NITRO REDUCTION ACTIVATION
SCHEME 9.33 Phosphoramidite-based prodrug for intracellular delivery of nucleotides
NUCLEOTIDE ACTIVATION
Anti-leukemia drug
SCHEME 9.34 Nucleotide activation of 6-mercaptopurine
Inhibits several enzymes in
the purine nucleotide
biosynthesis pathway.
PHOSPHORYLATION ACTIVATION
antiviral
2-deoxyguanosine
Resembles structure of 2-deoxyguanosine
Uninfected cells do not
phosphorylate acyclovir
(selective toxicity)
viral thymidine kinase
R = PO3=
viral guanylate kinase
R = P2O63viral phosphoglycerate kinase
R = P3O94-
Acyclovir triphosphate is a substrate for viral -DNA
polymerase but not for normal -DNA polymerase
Incorporation into viral DNA leads to a dead-end
complex (not active). Disrupts viral replication cycle
and destroys the virus.
Even if the triphosphate of acyclovir were released, it
is too polar to be taken up by normal cells.
High selective toxicity
RESISTANCE TO ACYCLOVIR
Modification of thymidine kinase
Change in substrate specificity for thymidine
kinase
Altered viral -DNA polymerase
Only 15-20% of acyclovir is absorbed
Therefore, prodrugs have been designed to
increase oral absorption.
Hydrolyzes
here
Prodrug for
a prodrug
adenosine deaminase
acyclovir
Hydroxylates
here
xanthine oxidase
acyclovir
This prodrug is 18 times more water soluble than
acyclovir.
A bipartate carrier-linked prodrug of acyclovir,
the L-valyl ester of acyclovir, has 3-5 fold higher
oral bioavailability with the same safety profile.
An analog of acyclovir whose structure is even
closer to that of 2-deoxyguanosine is ganciclovir.
More potent than acyclovir against human
cytomegalovirus.
Two carbon isosteres of ganciclovir are available.
C in place
of O
C in place
of O
Better oral absorption
than penciclovir
Converted to penciclovir
rapidly
SULFATION ACTIVATION
Activity of minoxidil requires sulfotransferase-catalyzed
sulfation to minoxidil sulfate.
hair growth
Inhibitors of the sulfotransferase inhibit the activity of
minoxidil, but not minoxidil sulfate.
DECARBOXYLATION ACTIVATION
An imbalance in the inhibitory neurotransmitter
dopamine and the excitatory neurotransmitter
acetylcholine produces movement disorders, e.g.
Parkinson’s disease.
In Parkinson’s there is a loss of dopaminergic
neurons and a low dopamine concentration.
Dopamine treatment does not work because it
cannot cross blood-brain barrier, but there is an
active transport system for L-dopa (levodopa,
8.133, R = COOH).
After crossing bloodbrain barrier
L-aromatic amino acid
decarboxylase (PLP)
dopamine (R = H)
Does not reverse the disease, only slows progression.
COMBINATION THERAPY
Monoamine oxidase B (MAO B) degrades
dopamine in the brain.
Therefore, a MAO B-selective inactivator is used
to protect the dopamine - selegiline (L-deprenyl).
Peripheral L-aromatic amino acid decarboxylase
destroys >95% of the L-dopa in the first pass.
Maybe only 1% actually gets into brain.
To protect L-dopa from peripheral (but not CNS)
degradation, inhibit peripheral L-aromatic amino
acid decarboxylase with a charged molecule that
does not cross the blood-brain barrier.
(used in U.S.)
(used in Europe and Canada)
Selectively inhibits peripheral L-amino acid decarboxylase.
The dose of L-dopa can be reduced by 75%.
SELECTIVE INACTIVATION OF BRAIN
MONOAMINE OXIDASE A
Earlier we found that inactivation of brain MAO A has an
antidepressant effect, but a cardiovascular side effect occurs
from inactivation of peripheral MAO A.
8.136 (R = COOH) is actively transported into the brain,
where L-aromatic amino acid decarboxylase converts it to
8.136 (R = H), a selective MAO A mechanism-based
inactivator. Carbidopa protects 8.136 (R = COOH) from
decarboxylation outside of the brain.
SELECTIVE DELIVERY OF DOPAMINE TO KIDNEYS
Dopamine increases renal blood flow.
Prodrugs were designed for selective renal vasodilation.
L-dopa
L--glutamyl-L-dopa
Dopamine accumulates in the kidneys because of
high concentrations of L--glutamyltranspeptidase
and L-aromatic amino acid decarboxylase there.
Example of a carrier-linked prodrug of a bioprecursor
prodrug for dopamine. SCHEME 9.35 Metabolic activation of L-γ-glutamyl-L-dopa
to dopamine