L22 Prodrugs SB Flashcards
What are Prodrugs?
Prodrugs are bioreversible derviatives of drug molecules thhat endergo enzymatic or chemical transformation in vivo to release the active parent drug, which can exert the desired pharmacological effect
What properties are prodrugs throught to improve?
Physiochemical, Biopharmaceutical and Pharmacokinetic properties.
okay. We know that there are Type 1 prodrugs and Type 2 prodrugs, but what other kinds classification is there?
Carrier linked prodrugs and bioprecursors.
A carrier linked prodrug is a prodrug is a prodrug that contains a chemical group that is enzymatically removed to reveal the true identity of a drug.
Ideally this group is pharmacology inactive and non-stable.
A bioprecursor is a compound that can be metabolised into a new compound that may be active or further metabolised -> to an active metabolite.
Why do carboxylic acids need to be converted to some thing else? and draw and state what theyre converted into
They can be deprotonated in vivo to produce the carboxylate anion and a proton. However, the carboxylate ion is negatively charged and the membrane is also negativit charged.
Hence it is likely that the drug will repel from the membrane. To prevent this repulsion, carboxylic acids can be converted into:
- Thio ester
- Double ester
- Ester
- Amide
The R groups of the ester can influence whether the group is electron donating or electron withdrawing, and this in turn can influence the rate of hydrolysis.
Whats the problem with amines? draw and state what their pro-forms are.
Amines can be protonated at physiological pH, therefore it can be charged. Charged drugs do not enter the cell membrane well, therefore the amine fuctional group can be modified into amides, carbamates and imines.
How do we modify alcohols? (draw + label)
Modified by reacting with carboxylic acids -> esters
Modified by reacting with a sulphate or a phosphate to make a phosphate ester.
A normal ester would be more hydrophobic (so can pass lipid bilayer), whereas phosphate or a sulphate ester would be more hydrophilic (so more soluble!)
what groups cause a slower rate of hydrolysis
bulky aliphatic groups and long alkyl chains. Sterically hindered ester or alcohols have a slow rate of hydrolysis.
Give the synthesis for an Amide prodrugs and its conversion back in vivo
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Give the synthesis for an Carbamate prodrugs and is conversion back in vivo
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make R-S(O)-CH3 less water soluble
R-S-CH3
make R-S(OO)NH2 more water soluble
RS(OO)NC(O)CH3CH2 - a carbamate switch. This is an electron withdrawing group
Electron-withdrawing groups on a compound
increase the susceptibility of hydrolysis and a cleavage of linkages.
give two examples of a prodrug and what features enhance its characteristics. Include any necessary drawings
Propfel - had poor water solubility. Then add Phosphate ester instead of OH group and solubility increases. Also No pain on injection with Fosprofol
Aciclovir’s OH group is replaced with amino acid valine (draw it). This increases bioavailability because of the PEPT1 Receptor, and also bioreversible.
