Prodrugs 2018 Prodrug – compound that is metabolised into pharmacologically active drug IUPAC definition: Compound that undergoes biotransformation before exhibiting pharmacological effect. Drug development barriers that can be overcome by prodrugs Improving solubility Improving solubility Improving solubility Improving solubility glucosides Improving solubility Polyethyleneglycol antibiotic roxithromycin, topic NSA Etofenamate Improving permeability Ideal ester/amide prodrug properties: Improving permeability carboxylic acid esters double esters are cleavaged more rapidly Improving permeability carboxylic acid esters - sartans Improving permeability carboxylic acid esters Improving permeability carboxylic acid esters – bacampicillin, pivampicillin 98-99% peroral absorption compared to 40% of ampicillin Improving permeability carboxylic acid esters levodopa methylester, enenalapril = ethylester Improving permeability carboxylic acid anhydrides clodronate anhydride Improving permeability Alcohol and phenol esters Improving permeability aldehydes and ketones: ethylene ketals spirothiazolidines oxime derivatives Improving permeability Nitrogen containing compounds imides, peptides Improving permeability Nitrogen containing compounds peptide prodrug of alpha adrenergic agonist Midodrine desglymidodrine = active metabolite Improving permeability Nitrogen containing compounds acidic nitrogen - unstable amides of fluorouracil and sulfonamides Improving permeability cyclic protection of neighbouring functional groups Improving permeability targeting transporters Prodrugs reducing metabolism carbamates of bambuterol are slowly hydrolyzed to terbutaline Prodrugs reducing metabolism docarpamine – orally available dopamine supply activated in liver Prodrugs reducing metabolism levormeloxifene is demetylated to active estrogen receptor modulator Prodrugs targeting tissue capecitabine predominantly metabolized in tumor cells 16x higher tumor concentration of 5-FU compared to plasma Prodrugs targeting tissue kidney-selective release of sulfamethoxazole peptide selective cleavaged by kidney enzymes Bioprecursors inactive molecules metabolised to active drug of different structure oxidative bioactivation of sulindac Bioprecursors oxidative bioactivation of provitamines provitamins are more stable and better orally absorbed Bioprecursors oxidative bioactivation of losartan Bioprecursors oxidative bioactivation of acyclovir precursor 6-deoxyacyclovir posses 6x better oral biovailability Bioprecursors oxidative activation of cyclophosphamide – active metabolites are reactive phosphamide and acrolein Bioprecursors reductive bioactivation of omeprazole in acidic environment Bioprecursors molsidomine is oxidatively deesterificated in liver to linsidomine. Linsidomine is plasma sensitive and releases NO Bioprecursors nitrates are converted by N-acetylcystein and glutathion to nitrites, nitrites are reduced and binds to nitrosothiols Soft drugs „antiprodrugs“ - Metabolically unstable functionality is introduced to shorten biological half-time - protects from system effect (and connected side effects) - controlled site of effect and time of duration Soft drugs locally administrated corticosteroids are destroyed in plasma Soft drugs Esmolol administred by infusion. Inactivated in plasma within 15 min.