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Prodrugs

Medicinal Chemistry I

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Prodrugs

Are inactive compounds converted to the active form in vivo.

Useful for drugs with undesirable physicochemical property.

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Undesirable Properties

• Physical Properties:a) Poor aqueous solubilityb) Low lipophilicityc) Chemical instabilityd) Acid Sensitivitye) Poor Membrane Permeability (poor absorption)f) Toxicity (non-selective bioactivity)g) Bad Tasteh) Short Duration of Actioni) Non-site specific

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Prodrugs activation mechanisms

• Variety of mechanisms by which prodrug can be converted into active drug:1. Metabolizing enzymes (phosphotase, esterases, peptidase)

• Interpatient variable

2. Chemical activation (Hydrolysis, decarboxylation, light activation)• Stability issues

3. Mixture of both

• Two important points:1. The prodrug should be effectively converted to the active form once

absorbed in the blood.2. Cleavable groups are non toxic.

Not all prodrugs are activated by metabolic enzymes. Photodynamic therapy involve the use of an external light to activate prodrugs.

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Prodrugs classification

• Can be classified into three categories: 1. Carrier-linked prodrugs

- Carrier-linked prodrugs are drugs that have been attached through a metabolically labile linkage to another molecule, the so-called promoiety, which is not necessary for activity but may impart some desirable property to the drug

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Prodrugs classification

2. Mutual prodrugs - In this type, both the drug and the

carrier has activity

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Produrgs classification

3. Bioprecursor prodrugs- contain no promoiety but rather rely on metabolism to introduce the functionality necessary to create an active species

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Carrier-linked prodrugs Prodrugs functional groups

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Prodrugs functional groups - Esters The most common type of prodrug because of the ease with

which the ester can be hydrolyzed or formed.

Esterase enzymes present in plasma and other tissues that are capable of hydrolyzing a wide variety of ester linkages

Can add lipophilicity or hydrophilicity to the drug

Increasing lipophilicity of the compound may yield a number of benefits, including increased absorption, decreased dissolution in the aqueous environment of the stomach, longer duration of action, and reducing bad taste

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Improve membrane permeability• Problem: - Epinephrine is poorly absorbed through eye tissues

- Catechols are unstable• Solution: The increased lipophilicity relative to epinephnine allows the

drug to move across the membrane of the eye easily and achieve higher intraocular concentrations

• The steric bulk of pivalic acid slows down the hydrolysis

HN

OH

OH

HO

Epinephrinepoor corneal membrane penetration

HN

OH

O

O

O

O

Dipivefrinbetter corneal penetration

Used in Glaucoma

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Improve Membrane Permeability Ampicillin is poorly absorbed from the GI tract

(~30% absorbed)WHY??? The carboxylic acid functional group (COOH): Binds the drug to a receptor via ionic or hydrogen

bonding. An ionizable group may prevent drug from

crossing a fatty cell membrane.Solution: Convert the acid function to an ester moiety. The less polar ester can cross fatty cell

membranes. The ester group will be hydrolyzed back to the

free acid by the esterase in the blood.

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Ampicillin activation In Vivo

Esterase

Esterase

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Masking bad taste• Problem: Water soluble drugs when dissolve in the mouth

could lead to bad taste- This cause low compliance (pediatric)

• Solution: A prodrug with reduced water solubility does not dissolve to any appreciable extent in the mouth and, therefore, does not interact with taste receptors.

Prodrugs for stability• Problem: propanolol undergo extensive first

pass metabolism (glucuronidation)• Solution: adding ester group on the alcohol

will protect it from metabolismO

OH

NH

Propranolol

Fisrt pass metabolism

O

O

NH

OOH

OBlood esterase

O

OH

NH

PropranololActive antihypertensive agent

O

O

NH

Propranolol O-glucuronide

OO

OH

OHHO

HO

Propanolol hemisuccinate

No fisrt pass metabolism by O-glucuronidation

Prodrugs for stability

OHO

N

O

OH

Naltrexoneused in the treatment of opioid addictionundergo extensive first-pass metabolism

OO

N

O

OH

OO

N

O

OH

OO

NO2

O

ONaltrexone anthranilate45 folds better orally available

Naltrexone acetylsalicylate28 folds better orally available

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Increasing hydrophilicity• Increase the water solubility of drugs, making them more

suitable for parenteral or oral administration when high water solubility is desirable

DrugO

O

Succinate esterIncreased water solubilityRapid Hydrolysis ( Relatively Unstable)

Drug

OS

O

O

ODrug

OP

O

O

O

Sulfate and phosphate esterIncreased water solubilityMore stable

OH

O

Clindamycin Phosphate

Improve membrane permeabilityPeptide carrier systems

NH

N

N

O

NH2N

OO

O

H2N H

L-valyl

Valaciclovir

NH

N

N

O

NH2N

OHO

Intestinal

absorption

Acyclovir in blood

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Improve membrane permeabilityPeptide carrier systems

Prodrug

Protein Carrier in BBB (Blood Brain Barrier)

Drugs with amine moiety

• The amide derivative is not a suitable choice in most of the case (WHY?)….Stable bond toward hydrolysis compared to the ester bond.

DrugHN

O

OR

DrugHN

O

R

Drug N

Carbamate Amide

Imine

Ar

Drug N

N Ar

Azo

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Drugs with amine moietyProdrug to increase lipophilicity

NNH2

OOH

F

ProgabideAnti-convulsant agent

H2NOH

O

GABAinhibitory neurotransmitter

Drugs with amine moietyProdrugs to increase water solubility

H2N

O

O

Benzocaine

NH

O

O

O

H3N

R

Benzocaine coupled with amino acidionized at physiological pH\

better water solubility

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Prolong The ActivityDiazepam

Prodrug

•Sustained Action•N-demethylation Metabolism

Hexobarbitone

N NH

Me

O O

O

Me

Cyclophosphoramide for phosphoramide mustard (anticancer agent)

Prodrugs to mask toxicity and side effects

Cyclophosphoramide• Non toxic• Orally active

Phosphoramide mustard• Alkylating agent

1. Cyt P450 2. Phosphoramidase

(liver)

O

P

NH O

N

Cl

Cl

HO

P

Cl

Cl

N

OH2N

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Azo prodrugs from amine

NHN

SO O

N N

OH

COOH

SulfasalazineUsed in ulcerative colitis

Azoreductase

released by colorectal bacteria

NHN

SO O

NH2

H2N

OH

COOH

Sulfapyridine

Aminosalicylic Acid

Prodrugs used to target drugs

Example:Hexamine

• Stable and inactive at pH>5• Stable at blood pH• Used for urinary infections where pH<5 • Degrades at pH<5 to form formaldehyde (antibacterial agent)

NN

N

N

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Bioprecursor prodrugs

• Bioprecursor prodrugs mostly use either oxidative or reductive activation reactions.

• The main activation pathways are:1) Proton activation.2) Hydrolytic activation3) Elemination activation4) Oxidative activation5) Reductive activation6) Nucleotide activation7) Phosphorylation activation8) Sulfation activation9) Decarboxylation activation

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Reduce toxicityNabumetone

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Reduce toxicityIdoxuridine phosphorylation

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Most other antiviral requires the same activation mechanism

N

NN

N NH2HO

OHPenciclovir

Viralthymidinekinase

N

NN

N NH2P O

OH

Cell kinases

N

NN

N NH2O

OH

PPP

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Proton Pump Inhibitor ActivationOmeprazole

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Bioluminescent Red Tide

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