Lec 3 Applications of Prodrugs PDF

Lec 3 Applications of Prodrugs Prodrugs 1.5.1 Prodrugs to improve membrane permeability  Improve Membrane Permeability  Ampicillin is poorly absorbed from the GI tract (~30% absorbed) WHY???  The carboxylic acid fun...

Lec 3 Applications of Prodrugs Prodrugs 1.5.1 Prodrugs to improve membrane permeability  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. 12/22/2020 4  Ampicillin activation In Vivo 12/22/2020 5 1.5.1 Prodrugs to improve membrane permeability Example:  1.5.1 Prodrugs to improve membrane permeability    12/22/2020 7 1.5.1 Prodrugs to improve membrane permeability 1.5.1.2 N-Methylation of amines Used to reduce polarity of amines Demethylated in liver Example: 1.5.1 Prodrugs to improve membrane permeability 1.5.1.3 Trojan Horse Strategy Example: Levodopa for dopamine Dopamine Levodopa Useful in treating Parkinson’s Disease More polar butis an amino acid Too polar to cross cell membranes Carried across cell membranes and BBB by carrier proteins for amino acids Decarboxylated in cell to dopamine  Cell Cell Membrane Membrane RECEPTOR Carrier Protein Cell Shoeb Alahmad  Cell Cell Membrane Membrane RECEPTOR Cell Shoeb Alahmad  Cell Membrane Cell Shoeb Alahmad  Cell Membrane Cell 1.5.2 Prodrugs to prolong activity 1.5.2.1 Mask polar groups Example: 6-Mercaptopurine Azathioprine (suppresses immune response) Slow conversion to 6-mercaptopurine Short lifetime - eliminated too quickly Longer lifetime  6-mercaptopurin suppresses the body’s immune response and is, therefore, useful in protecting donor graft s. Unfortunately, the drug tends to be eliminated from the body too quickly. The prodrug azathioprine is slowly converted to 6- mercaptopurine by being attacked by glutathione allowing a more sustained activity. The rate of conversion depends on the electron- withdrawing ability of the heterocyclic group. The greater the electron-withdrawing power, the faster the breakdown. The NO 2 group is therefore present to ensure an efficient conversion to 6-mercaptopurine, as it is strongly electron-withdrawing on the heterocyclic ring. 12/22/2020 31 1.5.2 Prodrugs to prolong activity Example: Valium for nordazepam Sustained Action N-Demethylation Valium Nordazepam 1.5.2 Prodrugs to prolong activity 12/22/2020 33 1.5.2 Prodrugs to prolong activity 1.5.2.2 Add hydrophobic groups Example: Cycloguanil Pamoate 1.5.2 Prodrugs to prolong activity Example: Fluphenazine decanoate This prodrug is administered once every 2 weeks 1.5.3 Prodrugs to mask toxicity and side effects Salicylic acid Aspirin Analgesic, but causes stomach Phenol masked by ester ulcers due to phenol group Hydrolysed in body 1.5.3 Prodrugs to mask toxicity and side effects Example: Cyclophosphoramide for phosphoramide mustard (anticancer agent) Phosphoramidase (liver) Cyclophosphoramide Non toxic Orally active 1.5.3 Prodrugs to mask toxicity and side effects Many important antiviral drugs such as aciclovir and penciclovir are non-toxic prodrugs which show selective toxicity towards virally infected cells. This is because they are activated by a viral enzyme which is only present in infected cells 12/22/2020 38 1.5.3 Prodrugs to mask toxicity and side effects Example: Phophorated penciclovir First phosphorylation requires viral thymidine kinase Only activated in virally infected cells Non-toxic to uninfected cells  1.5.3 Prodrugs to mask toxicity and side effects Example: a) Aminopeptidase b) Cyclisation removal of lysine LDZ Diazepam Avoids drowsy side effects of diazepam 1.5.3 Prodrugs to mask toxicity and side effects 12/22/2020 41 1.5.4 Prodrugs to lower water solubility 1.5.4 Prodrugs to lower water solubility Example: Palmitate ester Esterase Chloramphenicol  Example: Succinate ester Esterase Chloramphenicol  1.5.5 Prodrugs to increase water solubility 12/22/2020 45 1.5.5 Prodrugs to increase water solubility Example: Less painful on injection 1.5.5 Prodrugs to increase water solubility Example: Lysine ester of oestrone is better absorbed orally than oestrone Increased water solubility prevents formation of fat globules in gut Better interaction with the gut wall Hydrolysis in blood releases oestrone and a non toxic amino acid 1.5.7 Prodrugs to increase chemical stability Chemical stability is necessary parameter for every therapeutic agent to elicit its pharmacological activity for a longer duration. A shelf life of at least 2 years is desirable except for vaccines, cytotoxic agents and other life saving drugs. Although chemical unstability can be solved to a greater extent by appropriate formulations, its failure necessitates the use of prodrug approach. The prodrug approach is based on the modification of the functional group responsible for the instability or by changing the physical properties of the drug resulting in the reduction of contact between the drug and the media in which it is unstable 1.5.7 Prodrugs to increase chemical stability This approach was successfully used to inhibit the auto aminolysis, which occur due to capability of NH2 group of side chain to attach β–lactam ring of other molecule, in ampicillin molecule in concentrated solution it generates polymeric species of ampicillin. By making hetacillin, a prodrug of ampicillin formed by the reaction of acetone and ampicillin „ties up‟ the amine group and thus inhibits auto aminolysis. 1/20/2019 43 1.5.7 Prodrugs to increase chemical stability Example:  1.5.8 Prodrugs activated by external influences sleeping agents 12/22/2020 52 1.5.8 Prodrugs activated by external influences -sleeping agents 12/22/2020 54 12/22/2020 55 1.5.6 Prodrugs used to target drugs Example: Stable and inactive at pH>5 Stable at blood pH Used for urinary infections where pH