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  1. 1. 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
  2. 2. 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
  3. 3. Conversion of ProdrugsMetabolism (enzyme dependant)Chemical Methods (non-dependant) Hydrolysis Decarboxylation NOT patient dependant! Stability/Storage issues
  4. 4. 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 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
  5. 5. Chloramphenicol OH Cl H N Cl OH Cl H O N Esterase O2 N O Cl H OO2 N O O-Na+ or Water O OH O O-Na+ O 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
  6. 6. OPO3Na2 OH H3C H3C Sodium phosphate and O Carbon dioxideCl HO N O Cl Estermustine Sodium Phosphate Cl Emcyt® - Pharmacia & Upjohn NH NH+Cl- Aziridine Cl Cl Nornitrogen mustard 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
  7. 7. • Carboxylic acids and Alcohols: Most common type of prodrug O O Promoiety + HO Promoiety Drug O Drug OH or O O Promoiety O Drug + HO Drug Promoiety OH• 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
  8. 8. H3C NH(CH3)2+-SO4 CH3 O CH3 Erthromycin estolate O O O Ilosone® - Eli Lilly H3C CH3 HO O caps,tabs, suspension HO HO Antibiotic used to treat H3C CH3 O upper and lower respiratory O OMe infections (URI or LRI), CH3 CH3 Legionnaires disease, O O CH3 skin infections H3C OH• 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 aftertaste and is acid stable
  9. 9. H H R1 N S CH3 O N CH3 O CO2R2R2 = ethyl, propyl, butyl, phenylPenicillin esters Esterases NO REACTION! H H R1 N S O N O R3 CO2R2R2 = ethyl, propyl, butyl, phenylCephalosporin esters
  10. 10. OMeWhy? Vantin® – Pharmacia & Upjohn H H N N SIncrease H2 N URI, UTI, Gonorrhea, skinabsorption S infections O N OMeAvoid acid O Taking with food CH3 Ocatalyzed Esterase O O CH3 increases absorptiondecomposition O O CH3 CH3 OMe H H HO-Esterase N N S H2 N S O N OMe H 2O O CH3 CH3 O O CO2 + HO O H CH3 H3C OMe N H H H2 N N S S CH3 O N OMe O + O CH3 Active Drug O O
  11. 11. O-Na+ O O OH OH Drug O Drug + O Na+O- O O H+ O O Sodium succinate prodrug Sodium succinate Unstable: use immediatelyMore stable: less prone to hydrolysis by water O O O Sulfatase HO Drug S S O-Na+ OH + O Drug O-Na+ O Sulfate prodrug O O O Phosphatase HO Drug P P O-Na+ OH + HO Drug O-Na+ HO Phosphate prodrug
  12. 12. Amides not used due to high stabilityMost common amine derivative used is a Mannich Base prodrug H 3C HN CH3 H2 N H N S CH3 Water N S CH3 O CH3 CH3 + H3 C CH3 O N O N O CO2H O CO2H Acetone Hetacillin Ampicillin H3C OH N(CH3)2 Formaldehyde OH + -H2O O H2 C N NH2 + HN H H O Iminium OH O O H O O ion Pyrrolidine HTetracycline H3 C OH N(CH3)2 OH Rolitetracycline - A prodrug of H N N tetracycline with increased O OH O O H O O water solubility H
  13. 13. Mannich Base ChemistryMannich Reaction - This is nucleophilic addition reaction of an aldehyde and atleast a secondary amine to produce what is known as a schiff base onprotonation and elimination of a water molecule. The Schiff base is oftenstabilized by resonance. The addition of a carbanaion to the schiff base givesanother base called the Mannich base. The Mannich base formed can readilyeliminate the secondary amine to give the synthetic usefulness of the reaction,but when primary amines or ammonia are used the hydrogen on nitrogen atomcan participate in a further reaction to give more complex products.
  14. 14. •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 CO2H Sulfapyridine NHSO2 N N OH NHSO2 NH2 N NSulfasalazine - Azulfidine® - Pharmacia & Upjohn +Sulfonamide antibiotic and antiinflammatoryUsed to treat Ulcerative colitis, rheumatoid arthritis CO2H H2N OH 5-aminosalicylic acid
  15. 15. Aldehyde and ketone derivatives Little clinical utility with one exception N Acidic urine pH O 6 + 4 NH3 N H HN N Methenamine hippurate Hiprex® - Hoechst Marion Roussel Urex ® - 3M Pharmaceuticals plus a number of combos Used for prophylaxis or suppression/elimination of frequent UTI
  16. 16. 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) Reductive Phosphorylation (antiviral agents) Oxidation Example – Nabumetone – Relafen® – Smith Kline Beecham O Series of oxidative OH CH3 OCH3O decarboxylation CH3O Non-steroidal Active form of the drug antiinflammatory that inhibits Prostaglandin biosynthesis by Use: Arthritis cyclooxygenase
  17. 17. Reduction example - Mitomycin C - Mutamycin® - Bristol Myers Adenocarcinoma of the stomach and pancreas H2N H2N H2N O O O O O OH O O H H H H2 N OMe Reduction H2N OMe -OCH3 H2 N N NH N NH NH H3 C H3C H3 C N + O OH A quinone - A hydroquinone - electron withdrawing electron donating -H+ H+ DNA H2N DNA OH OH O H2 N -CO2H2 N OH O NH H2 N NH H3 C N -NH3H3 C N + OH N NH OH H3 C Electrophile OH Further alkylation
  18. 18. Phosphorylation example – H O O H N N O I O O I Viral ThymidineHO O P O O O Kinase O Not lipid soluble OH OHIodoxuridine - Herplex®Allergan - lipid soluble!Opthalmic product for ATPHerpes simplex keratitis OHigher affininty for viral H Nkinases than mammalian O O O O Ikinases but some toxicity -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
  19. 19. 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 target site Limit side effects and increase effectiveness
  20. 20. 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 environmentEspecially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents
  21. 21. 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
  22. 22. 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 HO HO Decarboxylase CO2H NH2 HO HO NH2 Dopamine Brain has a specific transport system for L-amino acids Dopamine does not cross the blood brain barrier efficiently, is rapidlymetabolized by oxidative deamination, and can cause peripheral side effects
  23. 23. Thank you

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