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Prodrugs• Definition: • A pharmacologically inactive chemical entity that when metabolized or chemically transformed by a
mammalian system is converted into a pharmacologically active
substance
• Why use prodrugs?– Improve patient acceptability (decrease pain on
injection)– Alter and improve absorption– Alter biodistribution– Alter metabolism– Alter elimination
Types of Prodrugs
• I. Carrier-linked prodrug
• A compound that contains an active drug linked to a carrier group that is removed enzymatically
• II. Bioprecursor prodrug• metabolized into a new compound that may itself be active or further metabolized to an active metabolite (e.g. amine to aldehyde to carboxylic acid).
Carrier-linked prodrug
• Carrier-linked prodrugs can be further subdivided into
• 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
EX FOR CARRIER LINKED BIPARTATE PRODRUGS
• Prodrugs for increased water solubility• Prodrugs for improved absorption &
distribution• Prodrugs for site specificity• Prodrugs for stability
Prodrugs for increased solubility
• Artemisinin is an antimalarial drug that is insoluble in water. Their succinic acid ester derivative artesunate is water soluble and can be used for parenteral use.
ArtesunateArtemisinin
Chloramphenicol
NH
Cl
OO
O-Na+O
O
ClOH
O2N
NH
Cl
OH
O
ClOH
O2N
O-Na+O
O
OH
Esterase
or Water
Chloramphenicol Succinate
Chloramphenicol
Sodium succinate
• Enzymatic and intramolecular spontaneous hydrolysis
• Increased water solubility, ester itself is inactive as an antibiotic
• Promoiety should be nontoxic and easily excreted
• Type of promoiety chosen is a function of properties desired
Prodrug for improved absorption and distribution
• Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen
• Baclofen is a racemic GABA(B) receptor agonist • This conversion seems to be primarily catalyzed in human tissues by human
carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells.
• Baclofen is used for treating spasm of skeletal muscles.
Arbaclofen placarbil
carboxylesterase-2
(R)-Baclofen
fluocinolone acetonide (R = H)fluocinonide (R = COCH3)
8.14
O
OCH3
HOCH3
OOR
F
F
OCH3
CH3
corticosteroids - inflammation, allergic, pruritic skin conditions
• Prodrugs for Improved Absorption and DistributioProdrugs for Improved Absorption and Distributionn
• Dipivefrin is a prodrug for the antiglaucoma drug epinephrine.The dipivaloyl esters allow for greater corneal permeability which are hydrolyzed by corneal and aqueous humor esterases.
Prodrug for Site specificity• The blood-brain barrier prevents hydrophilic molecules from
entering the brain, unless actively transported. The anticonvulsant drug vigabatrin crosses poorly. A glyceryllipid (R = linolenoyl) containing one GABA ester and one vigabatrinester was 300 times more potent in vivo than vigabatrin.
Vigabatrin
Prodrug for Site specificity• Oxyphenisatin is a bowel stimulant and is only active
when administered rectally.• Acetylation (protection) of the hydroxyls allow the drug to
be administered orally which is then hydrolysed at the desired site of action, the intestines.
Oxyphenisatin acetateOxyphenisatin
Prodrugs for Site Specificity.Prodrugs for Site Specificity.Oxyphenisatin is a bowel sterilant that is only active when administered rectally. Acetylation (protection) of the hydroxyls allow the drug to be administered orally which is then hydrolyzed at the desired site of action, the intestines.
Prodrugs for StabilityProdrugs for StabilityProdrugs may protect a drug from 1st-pass effects.Propranolol (antihypertensive drug) suffers from first-pass elimination resulting in decreased bioavailability of oral doses compared to i.v. injections. One of the major metabolites is the O-glucuronide. The hemisuccinate ester was designed to block glucuronide formation resulting in an 8-fold increase of plasma levels of propranolol.
Prodrug for Stabilityprotection from first-pass effect
Oral administration has lower bioavailability than i.v. injection.
propanolol (R = R' = H)8.22
OR'O NHCH(CH3 )2
R
prodrug R' =OCCH2 CH2COOH
antihypertension
plasma levels 8 times that with propanolol
Prodrugs to Minimize Toxicity
Many of the prodrugs just discussed also have lowered toxicity.
For example, epinephrine (for glaucoma) has ocular and systemic side effects not found in dipivaloylepinephrine.
Prodrug to Increase Patient Acceptance
The antibacterial drug clindamycin (8.28) is bitter and not well tolerated by children.
Clindamycin palmitate is not bitter.
clindomycin (R = H)clindomycin phosphate (R = PO 3H2)
clindomycin palmitate (R = O(CH 2)14CH3)8.28
N HCH3
H O
HN Cl
OHO
ORSCH3
OH
Either not soluble in saliva or does not bind to the bitter taste receptor or both.
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.
methenamine8.30
NN
N
N
CH2O + NH3H+
H3O+
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
Carrier Linker Drugenzyme
DrugLinkerCarrier +
spontaneous
Linker Drug+
Scheme 8.8
Tripartate Prodrugs of Ampicillin
ampicillin8.44
O
NNH2
NH
O
S
COO-
antibacterial
Various esters made were too stable in humans (although they were hydrolyzed in rodents) - thought the thiazolidine ring sterically hindered the esterase.
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.
Tripartate Prodrugs of Ampicillin
esterase
bacampicillin (R = CH 3 , R' = OEt)pivampicillin (R = H, R' = t-Bu)
8.45
8.46
..
+ R'COOH
whenR' = OEt
EtOH+ CO2
8.44
NH2N
SNH
OPh
O
OO O
R
R'
O
NH2N
SNH
OPh
O
OO
R
R H
O
OH
Scheme 8.10
98-99% absorbedAmpicillin is released in < 15 minutes
Mutual ProdrugsA bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked.
sultamicillin8.59
NH2
Ph
O O
NH S
NON
O
O
S
O
OO
O
Antibacterial ampicillin
-lactamase inactivatorpenicillanic 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.
Oxidative ActivationN-Dealkylation
Sedative 8.20
..
..P450P450
Cl
N N
N
N
CH3
CH3O
X
CH3
Cl
N N
N
N
CH3
HO
X
CH3
Cl
N N
N
NH2
CH3
O
X
NH
NN
NCH3
ClHO X
N
NN
NCH3
Cl
X
alprazoalam (X = H)triazolam (X = Cl)
8.77
-H2 O
O-DealkylationAnalgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.
phenacetin (R = CH2CH3)acetaminophen (R = H)
8.78
CH3HN
OR
O
N-Oxidation
+
pralidoxime chloride8.91
Cl - N
N
CH3
OH
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 (8.92).
+
pralidoxime chloride8.91
Cl - N
N
CH3
OH
oxidation into brain
8.92
NN
CH3
OH
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.
+
sulfapyridine8.108
8.107
sulfasalazine8.106
NNHSO2 N=N OH
COOH
H2N OH
COOH
NNHSO2 NH2
Reductive ActivationAzo Reduction
Scheme 8.29
ulcerative colitis
For inflammatory bowel disease
Causes side effects
Anaerobic cleavage by bacteria in lower bowel
To prevent side effect by sulfapyridine a macromolecular delivery system was developed.
8.109
n
N
SO2
NH
N
CO2Na
OH
poly(vinylamine)
spacer
Not absorbed or metabolized in small intestine.
NH2
CO2Na
OH Released by reduction at the disease site.
Sulfapyridine is not released (still attached to polymer).More potent than sulfasalazine.
Sulfoxide Reduction
sulindac8.111
CH3
CO2H
S
F
CH3
O
anti-arthritisSulindac 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.
sulindac8.111
CH3
CO2H
S
F
CH3
Oindomethacin
8.112
NCH3
CO2H
Cl
MeO
O
NH
HO
NH2
serotonin
Disulfide ReductionTo increase the lipophilicity of thiamin for absorption into the CNS.
+
+
GSH..
8.113H
thiamin8.114
N
N
NH2
N
HCH3
SO
OH
O
N
N
NH2
N
HCH3
S-
O
OH
N
N
NH2
NS
CH3N
N
NH2
N:S
CH3
OH
OH
S
B
OH
Scheme 8.30
nonenzymatic
poorly absorbed into CNS
Nucleotide Activation
8.123
hypoxanthine-guaninephosphoribosyltransferase
6-mercaptopurine8.122
N
N NH
N
SHO
HO
O—P—O—P—O-
OH
=O3PO O O
O- O-
N
N N
N
SH
O
HO OH
=O3PO
Anti-leukemia drugInhibits several enzymes in the purine nucleotide biosynthesis pathway.
Scheme 8.33
Phosphorylation Activation
acyclovir (R = H)8.124
HN
N N
N
O
H2N
ORO
8.125
HOO
NH2N
O
NHN
N
HO
antiviral 2-deoxyguanosine
Resembles structure of 2-deoxyguanosine
R = PO3=
viral guanylate kinase
viral thymidine kinase
R = P2O6-3
viral phosphoglycerate kinaseR = P3O9
-4
Uninfected cells do not phosphorylate acyclovir (selective toxicity)