Drug Discovery and Design 2 (prodrugs) Flashcards
What is a prodrug? What is it comprised of?
Inactive chemical derivative of a drug that must be BIOACTIVATED (Metabolised) in vivo to generate the pharmacologically bioactive/therapeutic form of the drug –> overcomes biological/pharmaceutical problem linked to its parent drug form
- Prodrug is typically drug linked to a prosthetic group or disposable transport facilitating system that serves to improve therapeutic use of the drug (Promoiety + Parent Drug)
Provide 9 reasons for the applications of prodrugs. Divide your answer by drug effectiveness and patient compliance.
Drug effectiveness
- Improve drug delivery and bioavailability
- Provide targeted or more selective drug action
- Alter the rate of drug onset or drug duration
- Improve drug physio-chemical properties
- Increase drug stability in formulation
- Reduce biodeactivation/metabolism of drug
Patient compliance
- Reduce drug toxicity and side-effects
- Decrease pain/irritation at injection sites
- Mask an unpleasant drug taste or odour
What is a promoiety? What are the two types of promoiety?
PROMOIETY IS A CHEMICAL GROUP/UNIT ADDITION OR MODIFICATION TO THE PARENT DRUG MOLECULE via reversible chemical processes undertaken on the drug –> should not exert and effect once released/altered to give parent drug
- Addition: involves conjugation of a chemical group to the parent drug molecule (disposable delivery facilitating group)
- Modification: involves chemically altering a group already on the parent drug molecule
What are the four stages required for the typical development of a prodrug?
- Identification of the problem(s) associated with the parent drug via biological in vitro and in vivo testing
- Identification of the physio-chemical group(s) and/or properties responsible for the parent drug problem(s)
- Selection and synthesis of a suitable prodrug candidate
- Biological testing of the prodrug candidate to verify that bioactivation effectively releases the active parent drug
What are some properties required for a prodrug? (provide at least 5)
- Prodrug should be pharmacologically INACTIVE
- Low or negligible toxicity for the prodrug and promoiety
- Parent drug must be generated in a controlled and quantitative manner from the prodrug in vivo (in organism)
- Capability of a functional group within the parent drug to undergo chemical synthesis
- Synthesis, isolation and purification of the prodrug must be relatively straightforward
- Moderate chemical and in vivo stability for the prodrug
- Good compatibility of the prodrug with components of the drug formulation
What biotransformation/metabolic processes are involved in the release of the bioactive parent drug from a prodrug?
- Hydrolysis: vast majority of prodrugs are bioactivated by endogenous hydrolytic enzymes. Also may occur via acid/base catalyzed chemical hydrolysis
- Oxidation: bioactivation mostly by oxidative hepatic enzymes (mainly CYP). Also may involve prodrug dealkylation e.g. removal of me/et groups
- Reduction: bioactivation by bioreducing enzymes
What are the three major types of prodrugs?
- Esters
- N-Mannich bases
- Amides
For Ester Prodrugs (most common);
A) How are they bioactivated?
B) How can an ester prodrug be made?
C) How do properties of parent drug change? How does it do this?
D) What are they used for (give 4 reasons)
A)
- hydrolytically bioactivated by ubiquitous esterase enzymes (enzymatic hydrolysis) or chemical hydrolysis
B)
- Ester prodrug can be made for any drug with a carboxylic acid CO2H or alcohol/phenol OH functional group (s)
C)
- Conversion of parent drug to ester prodrug typically alters its lipophilicity (log P) and polarity
- Parent drug CO2H or phenol group is neutralized and masked parent drug may only exist in unionized form (reduced acid irritability/toxicity issues)
D)
- Improve bioavailability of the parent drug
- Alter the solubility of the parent drug for formulation purposes (increase water solubility for parenteral use/delivery)
- Alter the stability of the parent drug
- Remove or reduce parent drug side-effect(s)
For ester prodrugs (most common);
A) What do long-chain alkyl and aryl esters do? What does this lead to?
B) What do ionizable esters do? What does this lead to?
C) What is the hydrolysis rate dependent on?
D) What do labile esters do? What does this lead to?
E) Examples of labile ester prodrugs are double ester prodrugs, what are the properties of this?
A)
- Increase drug lipophilicity –> may alter oral BA
- Elevate drug dermal absorption for topical use
- Highly lipophilic ester prodrugs = higher hydrolytic stability and may be used for depot purposes
- Drug hydrolysis rate can be altered by tailoring lipid solubility of added ester prodrug
B)
- Increase drug aqueous solubility for parenteral use/delivery
- Ionisable H2O-soluble ester prodrugs typically show low hydrolytic stability and may possess short shelf-life
C)
- Hydrolysis rate is temperature and pH-dependent
- High temp = more rapidly ester prodrugs will hydrolyze/bioactivate
- extremely low pH/ extremely high pH = faster hydrolysis
D)
- Labile (unstable) esters possess enhanced hydrolytic lability –> ester group is usually more prone to hydrolysis/activation.
- COO-R2 = R2 group is EWG (can be a phenyl group also)
- EWG increases hydrolysis
E)
- Unstable and readily hydrolyzed by esterases
For N-Mannich base prodrugs;
A) How can it be made?
B) How does it undergo bioactivation?
C) Why is it used (three reasons)?
D) What does of hydrolysis of N-mannich base prodrug depend on?
E) How is hydrolysis affected by pH?
A)
- Prodrug can be made for any drug containing NH group
- Prodrug synthesis is achieved by reaction of a parent drug NH group with aldehyde (e.g. CH2O) AND an amine
B)
- N-Mannich base prodrug usually undergo bioactivation via chemically mediated hydrolysis pathway
- May also undergo oxidative CYP enzymatic bioactivation
C)
- Alter the parent drug lipophilicity
- Alter the parent drug stability
- Increase the parent drug aqueous solubility
D)
- Parent drug N-H group pKa
- Steric hindrance (Size of added group)
- Basicity of added amino component
E)
- Prodrug hydrolysis normally increases with increasing pH i.e. most stable in acid solution
For amide prodrugs (least common);
A) How can it be made
B) How is it bioactivated
C) Why is it not used in a clincial setting
D) Why is it used sometimes
A)
- Can be made for any drug containing a Carboxylic acid CO2H or NH functional group
B)
- Bioactivated via enzymatic or chemical hydrolysis
C)
- Limited clinical use due to typically slow hydrolysis
D)
- Generally used to increase parent drug stability
What hydrolysis does;
A) ester prodrug undergo
B) n-mannich prodrug undergo
C) amide prodrug undergo
D) S=0 prodrug undergo
A) Chemical/enzymatic (esterase) hydrolysis
B) Chemical hydrolysis
C) Chemical/enzymatic (esterase) hydrolysis
D) Reduction (reductase)
Parent drugs
A) What prodrugs can phenol make?
B) What prodrugs can amine make?
C) What prodrugs can carboxylic acid make?
A) Ester
B) N-Mannich (with additional aldehyde and amine) and amide
C) Ester and amide prodrugs
Why are prodrugs required for antibacterial drugs? Provide 8 reasons
- Increase extent and rate of parent drug oral absorption
- Increase parent drug distribution to infected tissues
- Increase the biological half-life of the parent drug
- Increase the aqueous solubility of the parent drug for parenteral formulation/administration
- Decrease in vivo binding of the parent drug to food and plasma proteins
- Decrease the minimum inhibitory concentration (MIC) of the parent drug
- Decrease gastric degradation of the parent drug
- Decrease parent drug side-effects (inc. Improving taste)
Why are prodrugs required for anti-cancer drugs? Provide 6 reasons
- Prevent or minimize the in vivo deactivation (Metabolism) of the parent drug
- Prevent or minimize chemical degradation of the parent drug i.e. increase parent drug stability
- Increase the in vivo concentration of the parent drug within the tumor cells (increase drug selectivity)
- Remove or decrease the toxicity and/or side-effects associated with the parent drug
- Alter the physio-chemical properties of the parent drug for formulation purposes
- Improve the aqueous solubility of the parent drug for parenteral administration
