Post on 10-May-2015
Prodrug – Concept & Application
Prasented by – Ravindra Kumar GuptaLecturer , Department of Pharmaceutics
BR Nahata College Of Pharmacy , Mandsaur (M.P.)
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