Prodrug Strategy
Prodrug:
•
Definition: A pharmacologically inactive compound that is
converted to an drug by a metabolic biotransformation
•
Prodrug-drug transformation could be enzymatic or nonenzymic
•
Prodrug-drug conversion could occur before, during,
after absorption or at a specific site in the body
•
Ideally, conversion happens as soon as the target site is reached.
Reasons for Prodrug
1.
Solubility: some drugs are not soluble enough, attach a polar group to
increase solubility, deliver it to the target, activated metabolically.
2.
Absorption and distribution: adjust the drug’s polarity and lipophilicity
to escort it to the target
3.
Site specificity: in some cases, only certain organs can unmask a prodrug,
use of these prodrugs can significantly enhance site specificity.
4.
Instability: modify a drug that may be rapidly metabolized
5.
Drug duration: add a handle on a drug so it is activated slowly
6.
Toxicity: a drug may be toxic, can be masked, delivered to target site
and then unmasked
7.
Poor patient acceptibility: unpleasant taste or odor, produce gastric irritation or pain.
It can be modified to avoid these undesired properties
8.
Formulation problems: e.g. a volatile liquid can be solidified for
formulation as a tablet.
Definitions
Carrier-linked prodrug:
an active drug linked to a removable carrier
(usually hydrolyzable group such as ester, amide, etc.)
Bipartate prodrug: one carrier attached to one drug
Tripartate prodrug: one carrier connected to a drug through a linker
Mutual drug: two synergistic drugs attached to each other.
Bioprecusor:
A compound that is metabolized by molecular modification into a
new compound that is the active principle or which can be
metabolized further to the active drug
linker
Bipartate
Tripartate
Carrier-linked prodrug
biotransformation
Bioprecusor
Carrier-linked prodrug
A. Carrier linkages: alcohols and carboxylic acids
esterases are ubiquitous
degree of hydrophobicity and lipophilicity
variable stability by adjusting electronic or steric effects.
Carrier-linked prodrug
B. Amines
Amide not usually used because of high stability
Activated amide or AA conjugates more readily hydrolyzed
N-Mannich bases increase lipophilicity, variable hydrolysis rate
Schiff base, increase lipophilicity
OH
OH
CH3
OH
HN
CH3
O
N
F
NH
NH2
O
NH2
O
H2N
OH
Cl
Phenylpropanolamine
decongestant
N-Mannich prodrug
1
100
Lipophilicity
γ-aminobutyric acid
Neurotransmitter
unable to penetrate BBB
Schiff base prodrug
anticonvulsant Progabide
able to penetrate BBB
Carrier-linked prodrug
C. Carbonyl
Schiff base, acetals (ketals) increase lipophilicity
Oxime increase hydrophilicity
oxazolidines, thioxazolidines adjust lipophility.
Carrier-linked prodrug
2. Examples of Carrier-linked Bipartate Prodrugs
A. For Increased Water Solubility
O
H2N
O
Bezocaine
Local anesthetic
Low solubility
R= R’=H, Prednisolone
R= CH3, R’=H, Methylprednisolone
Both are water-insoluble
R
H
N
H3N
O
O
O
Ideal prodrug:
shelf life > 2 yrs;
activated < 10 min in vivo
Prodrug: R=CH3, R’=COCH2CH2CO2Na
shelf life<48hrs, others > 2 yrs
R=H, R’=phosphate, good
Bezocaine prodrug
stable, long shelf life
high solubility, activated readily
Bezodiazepine
Tranquilizer diazepam
Very low solubility
Open-chain prodrug for Bezodiazepine
Freely soluble in water
Benzodiazepine alprazolam
0.015mg/ml
Open-chain HCl salt, 109 mg/ml
Carrier-linked prodrug
2. Examples of Carrier-linked Bipartate Prodrugs
B. For Improved Absorption and Distribution
Cortisosteroid
Epinphrine, R = H
Inflammation,
Allergy
Pruritic skin conditions
Antiglaucoma
O
H2N
Carrier-linked prodrug
OH
2. Examples of Carrier-linked Bipartate Prodrugs
C. For Site Specificity
γ-aminobutyric acid
Neurotransmitter
unable to penetrate BBB
Bodor et al.
1983. Pharmacol. Ther. 19, 337
1987. Ann. N. Y. Acad. Sci. 507, 289
Glycerol lipid (R=linolenoyl
Bacterial meningitis
300 times as potent as
Vigabatrin
Carrier-linked prodrug
2. Examples of Carrier-linked Bipartate Prodrugs
D. For Stability
Naltrexone(R=H), opiod addiction
Not stable in the first pass
R= CO-o-NO2Ph, bioavailability 45 times
R= CO-o-AcOPh, bioavailability 28 times
E. Prolonged Release
Tolmetin sodium(R=O-Na+), antiarthritis
Peak concentration duration: 1 hr.
R= NHCH2COOH, peak duration: 9 hrs.
Carrier-linked prodrug
2. Examples of Carrier-linked Bipartate Prodrugs
F. To Minimize Toxicity
Aspirin: gastric irritation and bleeding
When R=CH2CONR1R2, no problems
G. To Encourage Patient Acceptance
Sulfa drug: pediatric antibiotics, bitter taste (R=H)
When R=CH3CO, tastless
H. Elimination of Formulation Problems
Prodrug for formaldehyde: release HCHO in acidic condition
Urine in bladder can be made acidic
Used as urinary tract antiseptic
Carrier-linked prodrug
3. Macromolecular Drug Carrier Systems
1.
2.
3.
4.
5.
6.
Protect drug until reaching target site
Localize drug to target site
Allow drug release
Minimize host toxicity
Biodegradable
Stable enough.
Target
Polyehtylene glycol
Polylysine
Cyclodextran
Albumin
etc.
Carrier-linked prodrug
4. Tripartate Prodrugs
General strategy
Example: ampicillin
Carrier-linked prodrug
4. Mutual Prodrugs
Two, usually synergistic, drugs attached to each other
+
Treat β-lactamase
producing bacteria
Pivampicillin
Absorbed, transported to the same site
Bioprecursor
A compound that is metabolized by molecular modification into a
new compound that is the active principle or which can be
metabolized further to the active drug
In vivo reactions that can activate a bioprecursor
•
Oxidative reaction
•
Reductive activation
•
Nucleotide activation
•
Phosphorylation activation
•
Decarboxylation activation
Bioprecursor
1. Oxidative reaction: P450 enzymes
A. N- and O-Dealkylations
Bioprecursor prodrug for alprazolam and triazolam, the tranquilizers
Bioprecursor
1. Oxidative reaction: P450 enzymes
B. Oxidative Deamination
Nitrogen mustard
Activation of cyclophosphamide: important cancer therapeutics
Bioprecursor
1. Oxidative reaction: P450 enzymes
C. N-Oxidation
?
Activation of procarbazine: cancer therapeutics against advanced Hodgkin’s disease
Bioprecursor
2. Reductive Activation:
A. Disulfide reduction
Activation of Thiamin bioprecursor prodrug
Bioprecursor
2. Reductive Activation:
B. Bioreductive Alkylation
Activation of anticancer antibiotic Mitomycin C
Bioprecursor
3.
Nucleotide activation
Anticancer agent
Acute childhood leukemias
de novo DNA synthesis
Incorporated into DNA after
nucleotide formation
4.
Phosphorylation activation
Acyclovir, antiviral drug
Genital herpes simplex virus &
varicella zoster virus infection
dG
Incorporated into DNA as a G after
Triple phosphorylation in infected cells
Normal cells unaffected
de novo DNA synthesis pathway
Acyclovir (R=H)
R=triphosphate, recognized as a dG by viral DNA polymerase
but not recognized by normal cellular DNA polymerase
Bioprecursor
3.
Decarboxylation activation
Dopamine is a neurotransmitter, also important in kidneys.
It increases systolic and pulse blood pressure and renal blood flow
To increase renal blood flow but without blood pressure increase,
it is desirable to deliver dopamine specifically to the kidneys
Rich in the kidneys
Overview
Carrier-linked prodrug:
Bipartate prodrug
Tripartate prodrug
Mutual drug
Bioprecusor:
Oxidative reaction
Reductive activation
Nucleotide activation
Phosphorylation activation
Decarboxylation activation
More reading materials:
Moody TW, et al. Development of high affinity camptothecin-bombesin conjugates
which have targeted cytotoxicity for bombesin receptor-containing tumor cells.
J. Biol. Chem. 2004, 279, 23580–23589.