Pro Drugs

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Prodrugs

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

Non-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 ACTIVE compounds that readily undergo metabolic inactivation to nontoxic products

Conversion of Prodrugs

Metabolism (enzyme dependant) Chemical Methods (non-dependant)

Hydrolysis Decarboxylation NOT patient dependant! Stability/Storage issues

Prodrugs

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 sitedirected delivery Advantages:

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

ChloramphenicolChloramphenicolOH OH Cl Cl O O-Na+ O O O H N O H O Cl Cl H N O

Esterase

O2N

O2N

or WaterOH O-Na+ O

Chloramphenicol Succinate

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 ProdrugH3CO Cl N O HO

OPO3Na2

H3C

OH

Sodium phosphate and Carbon dioxide

Cl

Estermustine Sodium Phosphate Emcyt - Pharmacia & Upjohn

Cl

NH

NH+Cl-

AziridineCl Nornitrogen mustard Cl

Actual alkylating species

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 prodrugO O Oor

Drug

Promoiety

Drug

OH

+

HO Promoiety

O

O O Drug

Promoiety

Promoiety

OH

+

HO Drug

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

Functional Groups in ProdrugsH3 C CH3 O O H3 C HO HO H3 C CH3 O O O O O NH(CH3)2+-SO4 CH3 Erthromycin estolate Ilosone - Eli Lilly caps,tabs, suspension Antibiotic used to treat upper and lower respiratory infections (URI or LRI), Legionnaire's disease, skin infections

HO

CH3 OMe O H3C CH3 OH

O CH3

CH3

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

Esters Failure as ProdrugsR1O O H N H

SN

CH3 CH3

CO2R2

R2 = ethyl, propyl, butyl, phenyl Penicillin esters R1O OCO2R2

Esterases NO REACTION!

H N

H N

S

R3

R2 = ethyl, propyl, butyl, phenyl Cephalosporin esters

b-Lactam prodrug Double estersWhy? Increase absorptionH 2N S NO O

OMeH N H NO S

Vantin Pharmacia & Upjohn URI, UTI, Gonorrhea, skin infections

OMeO CH3 O CH3 O O

Avoid acid catalyzed decomposition

Taking with foodCH3 CH3

Esterase OMe

increases absorption

H 2N S

NO

H N O

H NO

S

HO-Esterase OMe H 2O CO2

O H3C

CH3 O H

+

CH3 HO CH3

OMe H 2N S Active Drug NO OO O

H N

H N

S

OMe

+

CH3 O CH3

Other ester prodrugs - solubleO-Na+

ODrugOH

Drug

O O

O

+

O O

OH Na+OO O

H+

Sodium succinate prodrug

Sodium succinate

Unstable: use immediately More stable: less prone to hydrolysis by waterDrugO O O S O-Na+

Sulfatase Drug

OH

HO

+

O

O S O-Na+

Sulfate prodrug

Drug

O HO

O P O-Na+

Phosphatase DrugOH

HO

+

HO

O P O-Na+

Phosphate prodrug

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

H3C HN CH3 N S O O N

CH3 Water CH3 CO2 H

H2 N O

H N O N

S

CH3 CH3 + CO2 H

O H3C CH3

HetacillinN(CH3)2 OH NH2OH

AmpicillinFormaldehyde H 2C N+

Acetone

H 3C

OH

-H2O H

O H

+

HN Pyrrolidine

O

Tetracycline

O O H O H OH

O N(CH3)2 OH H N O

Iminium ion

H 3C

Rolitetracycline - A prodrug of N tetracycline with increased water solubility

OH

O

O O H O H

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 ProdrugsBacterial reductases reductive cleavage Release of 2 amine compounds Occurs in colon discourages small intestine systemic absorption Concentrates the drug at the desired site of actionSulfapyridineNHSO2 N

CO2HNHSO2 N

N N

OH

NH2

Sulfasalazine - Azulfidine - Pharmacia & Upjohn Sulfonamide antibiotic and antiinflammatory Used to treat Ulcerative colitis, rheumatoid arthritis H 2N

+CO2H OH

5-aminosalicylic acid

Carbonyl prodrugsAldehyde and ketone derivatives Little clinical utility with one exception

N Acidic urine pH N N N O 6 H H

+

4 NH3

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

Used for prophylaxis or suppression/elimination of frequent UTI

Bioprecursor Prodrugs

Do NOT contain a carrier or promoietyContain latent functionality Metabolically or chemically transformed into an active drug Types of activation at are predictableOxidative Reductive Phosphorylation

(most common method) (antiviral agents)

Oxidation Example Nabumetone Relafen Smith Kline BeechamO CH3

Series of oxidative decarboxylationCH3O

OH O

CH3O

Non-steroidal antiinflammatory Use: Arthritis

Active form of the drug that inhibits Prostaglandin biosynthesis by cyclooxygenase

Bioprecursor ProdrugsReduction example - Mitomycin C - Mutamycin - Bristol Myers Adenocarcinoma of the stomach and pancreasH 2N OO H 2N H 3C O

H 2N OOH

H 2N O -OCH3H2N H3C

H

O OMe N NH Reduction H2NH 3C

H

O OMe N NH

H

O

A quinone electron withdrawing

OH A hydroquinone electron donating

N +

NH

-H+ H+

OH H 2N H 3C

DNAH2N

OH

DNA -CO2 N + NH -NH3H2N H 3C OH OH

H 2N O O

N

NH

H3C OH

OH Further alkylation

N

NH

Electrophile

Bioprecursor ProdrugsPhosphorylation example H N O O I H N O I

HO

Viral Thymidine Kinase

O

O O O P O O O OH

Not lipid soluble

OH Iodoxuridine - Herplex Allergan - lipid soluble! Opthalmic product for Herpes simplex keratitis Higher affininty for viral kinases than mammalian kinases but some toxicity

ATPH N O I

O O O O -O P O P O P O O O O O OH

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

Chemical Delivery Systems

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 targe