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Chapter 8 Prodrugs and Drug Delivery Systems. The Organic Chemistry of Drug Design and Drug Action. Prodrugs and Drug Delivery Systems. Prodrug - a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation

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Chapter 8 prodrugs and drug delivery systems

Chapter 8

Prodrugs and Drug Delivery Systems

The Organic Chemistry of Drug Design and Drug Action

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

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

The organic chemistry of drug design and drug action

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

Types of ProdrugsDrug 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

Protecting Group Analogy for the Concept of Prodrugs

Scheme 8.1

analogous to


analogous to


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

Mechanisms of Prodrug ActivationCarrier-Linked Prodrugs

Most common activation reaction is hydrolysis.

Ideal drug carriers

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

Carrier Linkages for Various Functional GroupsAlcohols, 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

Prodrugs for Alcohol-Containing Drugs

Table 8.1

Ester analogs as prodrugs can affect lipophilicity or hydrophilicity

The organic chemistry of drug design and drug action

  • 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

Another approach to accelerate hydrolysis intramolecular hydrolysis of succinate esters

Another Approach to Accelerate HydrolysisIntramolecular hydrolysis of succinate esters

Scheme 8.2

The organic chemistry of drug design and drug action

Enolic hydroxyl groups can be esterified as well.

antirheumatic agent

Carboxylic acid containing groups esterify as with alcohols

Carboxylic Acid-Containing GroupsEsterify as with alcohols

Maintaining water solubility of carboxylate prodrugs

Maintaining Water Solubility of Carboxylate Prodrugs

Can vary pKa by appropriate choice of R and R

Prodrugs for phosphate or phosphonate containing drugs

Prodrugs for Phosphate- or Phosphonate-Containing Drugs

Amine prodrugs

Amine Prodrugs

Table 8.2

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)

The organic chemistry of drug design and drug action

N-Mannich base (R = CH2NHCOPh) has a log D7.4 two units greater than the parent compound.

The organic chemistry of drug design and drug action

Another approach to lower pKa of amines and make more lipophilic.

Imine (Schiff base) prodrug

hydrolyze imine and amide to GABA inside brain


A reductive carrier linked prodrug approach

A Reductive Carrier-Linked Prodrug Approach

Scheme 8.3

Prodrugs of sulfonamides

Prodrugs of Sulfonamides

A water soluble prodrug of the anti-inflammatory drug valdecoxib (8.9) has been made (8.10).

Prodrug analogs of carbonyl compounds

Prodrug Analogs of Carbonyl Compounds

Table 8.3




Acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract.

Examples of carrier linked bipartate prodrugs

Examples of Carrier-Linked Bipartate Prodrugs

The organic chemistry of drug design and drug action

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

Prodrug for Increased Water Solubility

Prodrug forms

for aqueous injection or opthalmic use

poor water solubility


The organic chemistry of drug design and drug action

To avoid formulation of etoposide with detergent, PEG, and EtOH (used to increase water solubility), it has been converted to the phosphate prodrug.

Prodrug for improved absorption through skin

Prodrug for Improved Absorption Through Skin

corticosteroids - inflammation, allergic, pruritic skin conditions

The organic chemistry of drug design and drug action

Better absorption into cornea for the treatment of glaucoma

The cornea has significant esterase activity

Prodrug for site specificity

Prodrug for Site Specificity

Bowel sterilant

(administer rectally)

Prodrug R = Ac (administered orally)

Hydrolyzed in the intestines

Prodrug for site specificity1

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 (8.17, R = linolenoyl) containing one GABA ester and one vigabatrin ester was 300 times more potent in vivo than vigabatrin.

Site specificity using enzymes at the site of action

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

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

The organic chemistry of drug design and drug action

Criteria for Success with Enzyme-Prodrug Therapies

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

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.




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


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

The organic chemistry of drug design and drug action

An example is carboxypeptidase G2 or alkaline phosphatase linked to an antibody to activate a nitrogen mustard prodrug.

Scheme 8.4

Humanization of antibodies minimizes immunogenicity. Note the prodrug-activating enzyme is a bacterial enzyme.

Antibody directed abzyme prodrug therapy adapt

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

Abzyme 38C2 Activation of a Doxorubicin Prodrug

Scheme 8.5

Gene directed enzyme prodrug therapy gdept also known as suicide gene therapy

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 8.6

Prodrug for stability protection from first pass effect

Prodrug for Stabilityprotection from first-pass effect

Oral administration has lower bioavailability than i.v. injection.


plasma levels 8 times that with propranolol

Prodrugs for slow and prolonged release

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

The organic chemistry of drug design and drug action


slow release

inject i.m.

Antipsychotic activity for about 1 month

Prodrugs to minimize toxicity

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.

Prodrug to increase patient acceptance

Prodrug to Increase Patient Acceptance

The antibacterial drug clindamycin (8.28) 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.

Prodrug to eliminate formulation problems

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.

Areas of improvement for prodrugs

Areas of Improvement for Prodrugs

  • site specificity

  • protection of drug from biodegradation

  • minimization of side effects

Macromolecular drug delivery

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

Disadvantages of Macromolecular Delivery Systems

  • Macromolecules may not be well absorbed

  • Alternative means of administration may be needed (injection)

  • Immunogenicity problems

Macromolecular drug carriers

Macromolecular Drug Carriers

Synthetic polymers

Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic.

Steric hindrance by polymer carrier

Steric Hindrance by Polymer Carrier


to enhance water solubility


No androgenic effect

Polymer backbone may be sterically hindering the release of the testosterone.

The organic chemistry of drug design and drug action

A spacer arm was added, and it was as effective as testosterone.

to enhance water solubility

Poly amino acid carriers

Poly(-Amino Acid) Carriers



norethindrone - contraceptive

Slow release over nine months in rats

General site specific macromolecular drug delivery system

General Site-Specific Macromolecular Drug Delivery System

either hydrophilic or hydrophobic

for site specificity

Site specific delivery of a nitrogen mustard

Site-Specific Delivery of a Nitrogen Mustard


spacer arm


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

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.


Antibody targeted chemotherapy

Antibody-Targeted Chemotherapy

Scheme 8.7

calicheamicin, except as disulfide instead of trisulfide



Does not release calicheamicinnonenzymatically.

Exhibits no immune response.

Tripartate drugs self immolative prodrugs

Tripartate Drugs(Self-immolativeProdrugs)

A bipartateprodrug may be ineffective because the linkage is too labile or too stable.

In a tripartateprodrug, 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

Tripartate Prodrugs

Scheme 8.8

Typical approach

Typical Approach

Scheme 8.9

Tripartate prodrugs of ampicillin

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.


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 ampicillin1

Tripartate Prodrugs of Ampicillin

Scheme 8.10

98-99% absorbed

Ampicillin is released in < 15 minutes

Reversible redox drug delivery system to the cns

Reversible Redox Drug Delivery System to the CNS

Scheme 8.11

hydrolysis activated

hydrolysis deactivated

hydrophilic drug

electron-withdrawing; hydrophilic


lipophilic carrier

Passive diffusion of 8.47 into the brain; active transport of 8.49 out of the brain

XH of the drug is NH2, OH, or COOH

If oxidation occurs before it gets into the brain, it cannot cross the blood-brain barrier.

The organic chemistry of drug design and drug action

When the drug is a carboxylic acid, a self-immolative reaction also can be used.

Scheme 8.12

Example of tripartate redox drug delivery

Example of Tripartate Redox Drug Delivery

-Lactams are too hydrophilic to cross the blood-brain barrier effectively.

Scheme 8.13

High concentrations of -lactams delivered into brain.

Another tripartate prodrug for delivery of antibacterials

Another Tripartate Prodrug for Delivery of Antibacterials

Permeases are bacterial transport proteins for uptake of peptides.

Scheme 8.14

Only L,L-dipeptides are active

Mutual prodrugs

Mutual Prodrugs

A bipartate or tripartateprodrug 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

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

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 bioprecursorprodrugs.

Protonation activation discovery of omeprazole

Protonation ActivationDiscovery 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 Discovery

Lead compound found in a random screen.

Liver toxicity observed thought to be because of the thioamide group.

Lead modification

Lead Modification

Related analogs made, and 8.61 had good antisecretory activity.

Modification gave 8.62 with high activity.

The sulfoxide (8.63) was more potent, but it blocked iodine uptake into the thyroid.

Lead modification cont d

Lead Modification (cont’d)

Modification of 8.63 gave 8.64 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 (8.65).

The organic chemistry of drug design and drug action

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 8.16

Formation of 8.66 leads to covalent attachment.

Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion.

Hydrolytic activation

Hydrolytic Activation

Hydrolysis can be a mechanism for bioprecursor prodrug activation, if the product requires additional activation.

Scheme 8.17

antitumor agent

prodrugs of leinamycin

The organic chemistry of drug design and drug action

Hydrolysis of these analogs gives an intermediate that reacts further to the activated form.

this was synthesized and gave 8.74 as well as DNA cleavage

increased stability over leinamycin

Scheme 8.18

Elimination activation

Elimination Activation

Scheme 8.19

potent inhibitor of dihydroorotate dehydrogenase

rheumatoid arthritis drug

Inhibition of dihydroorotate dehydrogenase blocks pyrimidine biosynthesis in human T lymphocytes.

Oxidative activation n dealkylation

Oxidative ActivationN-Dealkylation

Scheme 8.20

O dealkylation


Analgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.

Oxidative deamination

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.

Scheme 8.21

Cyclophosphamide was very effective, but it required liver homogenates (contains P450) for activation. Therefore oxidation is required, not hydrolysis.


N oxidation



advanced Hodgkin’s disease

Scheme 8.22


N oxidation1


Pralidoxime chloride is an antidote for nerve poisons.

It reacts with acetylcholinesterase that has been inactivated by organophosphorus toxins.

The organic chemistry of drug design and drug action

To increase the permeability of pralidoxime into the CNS, the pyridinium ring was reduced (8.92).

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 8.92 crosses the blood-brain barrier; oxidation to 8.91 prevents efflux from brain.

Mechanism of acetylcholinesterase

Mechanism of Acetylcholinesterase

Scheme 8.23

Inactivation of acetylcholinesterase by diisopropyl phosphorofluoridate

Inactivation of Acetylcholinesterase by Diisopropyl Phosphorofluoridate

Scheme 8.24

affinity labeling agent

irreversible inhibition

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

Reactivation of Inactivated Acetylcholinesterase by Pralidoxime

Scheme 8.25

The organic chemistry of drug design and drug action

Temporary inhibition of acetylcholinesterase enhances cholinergic action on skeletal muscle.

Scheme 8.26

covalent, but reversible inhibition

Used for the neuromuscular disease myasthenia gravis

The organic chemistry of drug design and drug action

Reversible (noncovalent) inhibitors of acetylcholinesterase, such as donepezil and tacrine are used for Alzheimer’s disease. Enhances neurotransmission involved in memory.

S oxidation


Poor oral bioavailability of brefeldin A. Converted to Michael addition sulfide prodrug (8.98). S-Oxidation and elimination gives brefeldin A.

Scheme 8.27

antitumor, antiviral agent

Aromatic hydroxylation cyclohexenones as prodrugs for catechols

Aromatic HydroxylationCyclohexenones as prodrugs for catechols

Scheme 8.28

aromatic hydroxylation

oxidation next to sp2 carbonyl

Alkene epoxidation

Alkene Epoxidation

active anticonvulsant agent



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).

The organic chemistry of drug design and drug action

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

Reductive ActivationAzo Reduction

Scheme 8.29

Anaerobic cleavage by bacteria in lower bowel

ulcerative colitis

For inflammatory bowel disease

Causes side effects

The organic chemistry of drug design and drug action

To prevent side effect by sulfapyridine a macromolecular delivery system was developed.


Not absorbed or metabolized in small intestine.


Released by reduction at the disease site.

Sulfapyridine is not released (still attached to polymer).

More potent than sulfasalazine.

Azido reduction

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

Sulfoxide Reduction


Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.

The organic chemistry of drug design and drug action

Sulindac is an indaneisostere 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

Disulfide Reduction

To increase the lipophilicity of thiamin for absorption into the CNS.

Scheme 8.30


poorly absorbed into CNS

The organic chemistry of drug design and drug action

To diminish toxicity of primaquine and target it for cells with the malaria parasite, a macromolecular drug delivery system was designed.

Intracellular thiol much higher than in blood; selective reduction inside the cell

antimalarial, toxic


for improved

uptake in liver

Therapeutic index of 8.116 is 12 times higher than 8.115 in mice.

Nitro reduction

Nitro Reduction

Scheme 8.32

Mechanism-based inactivator of thymidylate synthase

Nucleotide activation

Nucleotide Activation

Scheme 8.33

Anti-leukemia drug

Inhibits several enzymes in the purine nucleotide biosynthesis pathway.

Phosphorylation activation

Phosphorylation Activation



Resembles structure of 2-deoxyguanosine

viral thymidine kinase

Uninfected cells do not phosphorylate acyclovir (selective toxicity)

R = PO3=

viral guanylate kinase

R = P2O63-

viral phosphoglycerate kinase

R = P3O94-

The organic chemistry of drug design and drug action

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

Resistance to Acyclovir

Modification of thymidine kinase

Change in substrate specificity for thymidine kinase

Altered viral -DNA polymerase

The organic chemistry of drug design and drug action

Only 15-20% of acyclovir is absorbed

Therefore, prodrugs have been designed to increase oral absorption.

Hydrolyzes here

Prodrug for a prodrug

adenosine deaminase


The organic chemistry of drug design and drug action

Hydroxylates here

xanthine oxidase


This prodrug is 18 times more water soluble than acyclovir.

The organic chemistry of drug design and drug action

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.

The organic chemistry of drug design and drug action

An analog of acyclovir whose structure is even closer to that of 2-deoxyguanosine is ganciclovir.

More potent than acyclovir against human cytomegalovirus.

The organic chemistry of drug design and drug action

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

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

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).

The organic chemistry of drug design and drug action

After crossing blood-brain barrier

L-aromatic amino acid decarboxylase (PLP)

dopamine (R = H)

Does not reverse the disease, only slows progression.

Combination therapy

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.

The organic chemistry of drug design and drug action

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

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

Selective Delivery of Dopamine to Kidneys

Dopamine increases renal blood flow.

Prodrugs were designed for selective renal vasodilation.

Scheme 8.34



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 bioprecursorprodrug for dopamine.

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