Initial definition: A pharmacologically inactive chemical entity that when metabolized or chemically transformed by a mammalian system is converted into a pharmacologically active substance

“Drug Latentiation” – included later Process of purposely designing and synthesizing a molecule that

specifically requires “bioactivation” to a pharmacologically active substance

Why use prodrugs? Improve patient acceptability (decrease pain on injection) Alter and improve absorption Alter biodistribution Alter metabolism Alter elimination

Prodrugs

“Hard Drugs” - compounds that contain structural characteristics required for activity but are not susceptible to metabolism Increased efficiency by avoiding metabolism No toxic metabolites are formed HOWEVER, less readily eliminated due to lack of

metabolism “Soft Drugs” - These are the opposite of

prodrugs. These compounds are designed and synthesized as ACTIVEACTIVE compounds that readily undergo metabolic inactivation to nontoxic products

Non-Prodrugs

Conversion of Prodrugs Metabolism (enzyme dependant) Chemical Methods (non-dependant)

Hydrolysis Decarboxylation NOT patient dependant! Stability/Storage issues

Carrier-linked prodrugs – drugs that are attached through a metabolically labile chemical linkage to another molecule designated as the “promoiety” The “promoiety” alters the physical properites of the

drug to increase water or fat solubility or provide site-directed delivery

Advantages: Increased absorption Injection site pain relief Elimination of unpleasant taste Decreased toxicity Decreased metabolic inactivation Increased chemical stability Prolonged or shortened action

Prodrugs

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

Mutual Prodrug

Actual alkylating species

CH3

OH

OH

NHCl

Cl

NH+Cl-

ClNornitrogen mustard

Aziridine

Sodium phosphateandCarbon dioxide

CH3

OPO3Na2

ON

O

Cl

Cl Estermustine Sodium PhosphateEmcyt® - Pharmacia & Upjohn

• Used for metastatic carcinoma of the prostate

• Promoiety also a drug!

• Prodrug is selectively taken up into estrogen receptor positive cells then urethane linkage is hydroylzed

• 17-alphaestradiol slow prostate cell growth

• Nornitrogen mustard is a weak alkylating agent

Functional Groups in Prodrugs• Carboxylic acids and Alcohols: Most common type of prodrug

Drug OPromoiety

OOH Promoiety

Promoiety ODrug

O

Drug OH

O

Promoiety OH

O

OH Drug

or

+

+

• Types of esterase enzymes mediating the hydrolysis process

• Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase, Carboxypeptidase, Cholinesterase

• Bacterial microflora enzymes

• Wide number of choices of promoiety alcohols available

• Steric, electronic and hydrophobicity properties allow rate and extent of hydrolysis to be controlled

OCH3

O

O

O

O

OH

CH3

CH3O

CH3

CH3

CH3OH

CH3

CH3

OHO

O

CH3OHCH3

OMe

CH3

O

NH(CH3)2+-SO4

Erthromycin estolateIlosone® - Eli Lillycaps,tabs, suspension

Antibiotic used to treatupper and lower respiratoryinfections (URI or LRI), Legionnaire's disease,skin infections

• Erythromycin is a very bitter substance easily destroyed at acidic pH

• Propionate ester is to increase lipid solubility for improved absorption

• Ester must be hydrolyzed for antibacterial activity

• Lauryl sulfate salt – absorption not affected by food, less bitter after taste and is acid stable

Functional Groups in Prodrugs

Esters Failure as Prodrugs

N

SNH

OO

CO2R2

HR1

R3

R2 = ethyl, propyl, butyl, phenylCephalosporin esters

EsterasesNO REACTION!

N

SNH

OO

CO2R2

HCH3

CH3

R1

R2 = ethyl, propyl, butyl, phenylPenicillin esters

-Lactam prodrug – Double esters

N

S N

SNH

OO

HNH2

OMe

OMe

OO

CH3

O

OCH3

OCH3

CH3

N

S N

SNH

OO

HNH2

OMe

OMe

OOO

CH3

HCH3

OHCH3

CH3

CO2 +

N

S N

SNH

OO

HNH2

OMe

OMe

OO

OCH3

CH3

+

Active Drug

HO-Esterase

Esterase

H2O

Vantin® – Pharmacia & Upjohn

URI, UTI, Gonorrhea, skin infections

Taking with food

increases absorption

Why?

Increase absorption

Avoid acid catalyzed decomposition

Other ester prodrugs - soluble

Unstable: use immediately

+DrugO

O

O

O-Na+

Sodium succinate prodrug

H+

DrugOH

O

O

O

Na+O-O

O

OH

Sodium succinate

DrugO

PO

O-Na+OH DrugOH P

O

O-Na+

OH

OH+

Phosphatase

Phosphate prodrug

DrugO

SO

O O-Na+ DrugOH

SulfataseS

O

O O-Na+

OH+

Sulfate prodrug

More stable: less prone to hydrolysis by water

Amine derivatives as prodrugs Amides not used due to high stability Most common amine derivative used is a Mannich Base prodrug

WaterSNNH

CH3CH3

O

CH3

CH3

CO2HON

SNHNH2

O

CH3

CH3

CO2HON

Hetacillin Ampicillin

CH3 CH3

O

Acetone

+

CH3

OH

N(CH3)2OH

OOH OH

O

OH

O

NH2

-H2ON

+CH2

Iminium ion

H H

O

Formaldehyde

NH

Pyrrolidine

+

N

CH3

OH

N(CH3)2OH

OOH OH

O

OH

O

NH

Rolitetracycline - A prodrug of

tetracycline with increased

water solubility

Tetracycline

Mannich Base Chemistry

Mannich Reaction - This is nucleophilic addition reaction of an aldehyde and at least a secondary amine to produce what is known as a schiff base on protonation and elimination of a water molecule. The Schiff base is often stabilized by resonance. The addition of a carbanaion to the schiff base gives another base called the Mannich base. The Mannich base formed can readily eliminate the secondary amine to give the synthetic usefulness of the reaction, but when primary amines or ammonia are used the hydrogen on nitrogen atom can participate in a further reaction to give more complex products.

Azo Prodrugs•Bacterial reductases reductive cleavage

• Release of 2 amine compounds

• Occurs in colon discourages small intestine systemic absorption

• Concentrates the drug at the desired site of action

NNHSO2 N N OH

CO2H

Sulfasalazine - Azulfidine® - Pharmacia & UpjohnSulfonamide antibiotic and antiinflammatoryUsed to treat Ulcerative colitis, rheumatoid arthritis

NNHSO2 NH2

NH2 OH

CO2H

+

5-aminosalicylic acid

Sulfapyridine

Carbonyl prodrugs Aldehyde and ketone derivatives Little clinical utility with one exception

Methenamine hippurate Hiprex® - Hoechst Marion Roussel Urex ® - 3M Pharmaceuticals plus a number of combos

Used for prophylaxis or suppression/elimination of frequent UTI

NNN

N

Acidic urine pH

H H

O6 + 4 NH3

Bioprecursor Prodrugs Do NOT contain a carrier or promoiety

Contain latent functionality Metabolically or chemically transformed into an active drug Types of activation at are predictable

Oxidative (most common method) ReductivePhosphorylation (antiviral agents)

Oxidation Example – Nabumetone – Relafen® – Smith Kline Beecham

CH3

O

CH3O

OH

CH3OO

Series of oxidative

decarboxylation

Active form of the drugthat inhibits Prostaglandinbiosynthesis bycyclooxygenase

Non-steroidal antiinflammatory

Use: Arthritis

Reduction example - Mitomycin C - Mutamycin® - Bristol Myers Adenocarcinoma of the stomach and pancreas

N

O

O

NH2

CH3

O

NH2O

NH

OMeH

A quinone - electron withdrawing

-H+

-CO2

-NH3

Electrophile

DNA

NH2

CH3NHN

OH

OH

N

NH2

CH3

O

NH2O

NH

H

+

NH2

CH3

O

NH2O

NHN

OH

OH

H+

-OCH3

N

OH

OH

NH2

CH3

O

NH2O

NH

OMeH

A hydroquinone - electron donating

Reduction

DNA

NH2

CH3NHN

OH

OH+

Further alkylation

Bioprecursor Prodrugs

Phosphorylation example –

O

NH

O

O

I

OH

OPO

O

O

Viral Thymidine

KinaseO

NH

O

O

I

OH

OH

Iodoxuridine - Herplex®

Allergan - lipid soluble!Opthalmic product forHerpes simplex keratitisHigher affininty for viralkinases than mammaliankinases but some toxicity

O

NH

O

O

I

OH

OPO

O

O

POP-O

O

O

O

O

TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporated into DNA affording incorrect base pairing and template activity

ATP

Not lipid soluble

Bioprecursor Prodrugs

We have already seen 2 examples of this: Sulfasalazine – an azo compound Methenamine – An urinary antibacterial agent

Requirements Prodrug reach the site of action in high concentrations Knowledge of high metabolism at site Other factors

Extent of organ or site perfusion Information on the rate of prodrug conversion to the active form

at both target and non-target sites Rate of input/output of prodrug from the target site

Limit side effects and increase effectiveness

Chemical Delivery Systems

Types of carriers that have been used Proteins Polysaccharides Liposomes Emulsions Cellular carriers (erythrocytes and leukocytes) Magnetic control targeting Implanted mechanical pumps

What is the Basic Goal? Protect a non-specific biological environment from a drug Protect a drug from a non-specific biological environment Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents

Chemical Delivery Systems

The ideal situation: Prodrug readily transported to the site of action Prodrug is rapidly absorbed at the site Selective and rapid conversion to the active drug Kidney and Liver are easy targets due to high perfusion and

high metabolic rates Other tissue sites can be problematic for the same reasons

Drug migrate slowly (site of action to a site of excretion) Ideal situation is VERY complex to achieve

Example: Methenamine the lower the pH, the faster the rate of formaldehyde formed blood pH 7.4 therefore, little formaldehyde formed

Chemical Delivery Systems

Example: Cancer Chemotherapy Tumor cells have a much higher growth fraction This translates into higher enzymatic activity that can be exploited Target a prodrug to these sites and exploit higher enzyme activity

Example: L-Dopa or Levodopa – Anti-Parkinsonism agent Larodopa® – Roche and Dopar® - Procter & Gamble

Brain has a specific transport system for L-amino acids Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects

OH

OH

NH2

CO2H OH

OH

NH2

Decarboxylase

Dopamine

Chemical Delivery Systems