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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Prodrugs and Drug Delivery SystemsThe Organic Chemistry of Drug Design and Drug Action
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.
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
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
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
Keep in mind that a prodrug whose design is based on rat metabolism may not be effective in humans.
Most common activation reaction is hydrolysis.
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
Ester analogs as prodrugs can affect lipophilicity or hydrophilicity
Can vary pKa by appropriate choice of R and R
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
A water soluble prodrug of the anti-inflammatory drug valdecoxib (8.9) has been made (8.10).
Acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract.
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.
for aqueous injection or opthalmic use
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.
corticosteroids - inflammation, allergic, pruritic skin conditions
The cornea has significant esterase activity
Prodrug R = Ac (administered orally)
Hydrolyzed in the intestines
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.
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.
For selective activation of prodrugs in tumor cells
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 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
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
An example is carboxypeptidase G2 or alkaline phosphatase linked to an antibody to activate a nitrogen mustard prodrug.
Humanization of antibodies minimizes immunogenicity. Note the prodrug-activating enzyme is a bacterial enzyme.
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.
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.
Oral administration has lower bioavailability than i.v. injection.
plasma levels 8 times that with propranolol
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
Antipsychotic activity for about 1 month
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.
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.
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.
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.
Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic.
to enhance water solubility
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
norethindrone - contraceptive
Slow release over nine months in rats
either hydrophilic or hydrophobic
for site specificity
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).
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.
calicheamicin, except as disulfide instead of trisulfide
Does not release calicheamicinnonenzymatically.
Exhibits no immune response.
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.
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.
Ampicillin is released in < 15 minutes
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.
When the drug is a carboxylic acid, a self-immolative reaction also can be used.
-Lactams are too hydrophilic to cross the blood-brain barrier effectively.
High concentrations of -lactams delivered into brain.
Permeases are bacterial transport proteins for uptake of peptides.
Only L,L-dipeptides are active
A bipartate or tripartateprodrug in which the carrier is a synergistic drug with the drug to which it is linked.
penicillanic acid sulfone
Hydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone : formaldehyde
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.
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 compound found in a random screen.
Liver toxicity observed thought to be because of the thioamide group.
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.
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 reaction also can be used.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.
Formation of 8.66 leads to covalent attachment.
Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion.
Hydrolysis can be a mechanism for bioprecursor prodrug activation, if the product requires additional activation.
prodrugs of leinamycin
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
potent inhibitor of dihydroorotate dehydrogenase
rheumatoid arthritis drug
Inhibition of dihydroorotate dehydrogenase blocks pyrimidine biosynthesis in human T lymphocytes.
Analgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.
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.
advanced Hodgkin’s disease
Pralidoxime chloride is an antidote for nerve poisons.
It reacts with acetylcholinesterase that has been inactivated by organophosphorus toxins.
To increase the permeability of reacts further to the activated form.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.
affinity labeling agent
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.
Temporary inhibition of Pralidoximeacetylcholinesterase enhances cholinergic action on skeletal muscle.
covalent, but reversible inhibition
Used for the neuromuscular disease myasthenia gravis
Reversible ( Pralidoximenoncovalent) inhibitors of acetylcholinesterase, such as donepezil and tacrine are used for Alzheimer’s disease. Enhances neurotransmission involved in memory.
Poor oral bioavailability of brefeldin A. Converted to Michael addition sulfide prodrug (8.98). S-Oxidation and elimination gives brefeldin A.
antitumor, antiviral agent
oxidation next to sp2 carbonyl
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).
Arylglyoxylic Pralidoxime 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).
Anaerobic cleavage by bacteria in lower bowel
For inflammatory bowel disease
Causes side effects
To prevent side effect by Pralidoximesulfapyridine 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.
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.
Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.
Sulindac Pralidoxime 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.
To increase the lipophilicity of thiamin for absorption into the CNS.
poorly absorbed into CNS
To diminish toxicity of Pralidoximeprimaquine 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
uptake in liver
Therapeutic index of 8.116 is 12 times higher than 8.115 in mice.
Mechanism-based inactivator of thymidylate synthase
Inhibits several enzymes in the purine nucleotide biosynthesis pathway.
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-
Acyclovir triphosphate is a substrate for viral Pralidoxime-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
Modification of thymidine kinase
Change in substrate specificity for thymidine kinase
Altered viral -DNA polymerase
Only 15-20% of acyclovir is absorbed Pralidoxime
Therefore, prodrugs have been designed to increase oral absorption.
Prodrug for a prodrug
Hydroxylates Pralidoxime here
This prodrug is 18 times more water soluble than acyclovir.
A Pralidoximebipartate 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 that of 2isosteres of ganciclovir are available.
C in place of O
C in place of O
Better oral absorption than penciclovir
Converted to penciclovir rapidly
Activity of minoxidil requires sulfotransferase-catalyzed sulfation to minoxidil sulfate.
Inhibitors of the sulfotransferase inhibit the activity of minoxidil, but not minoxidil sulfate.
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 blood-brain barrier that of 2
L-aromatic amino acid decarboxylase (PLP)
dopamine (R = H)
Does not reverse the disease, only slows progression.
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 that of 2L-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%.
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.
Dopamine increases renal blood flow.
Prodrugs were designed for selective renal vasodilation.
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.