adi

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)