49 Questions
What is the main purpose of a carrier prodrug?
Enhance chemical and biological characteristics of the drug
In prodrug design, why are simple aliphatic or aromatic esters not preferred?
As they are not labile enough in vivo, resulting in poor conversion of the pro-drug
What issues can a prodrug help resolve?
Improving patient compliance
What is the classification based on in broad classification of prodrugs?
Based on acid sensitivity
Why are carrier prodrugs formed by combining an active drug with a carrier?
To form a compound with desired chemical and biological characteristics
What is the key advantage of a bioprecursor prodrug?
The active drug is already present within its structure
What is the purpose of using drug carbidopa in conjunction with levodopa for Parkinson's treatment?
To prevent the degradation of levodopa by dopa decarboxylase before it reaches the brain
Why is it challenging to use peptides and proteins directly as drugs?
They are too large and highly charged to easily cross into cells
Why are antibodies important in drug therapy?
They can be used to target specific cells or parts of the body for drug delivery
Which strategy is NOT used to optimize access to a drug target?
Using endogenous compounds directly as drugs
What is a key concern regarding the use of natural hormones as drugs?
They are susceptible to adverse immune reactions when administered orally
How are oligonucleotides stabilized for drug development?
By modifying their sugar-phosphate backbone to avoid enzymatic recognition
What is the main advantage of designing prodrugs for drug delivery to the brain?
Crossing the blood-brain barrier
Why are prodrugs linked to a polymer for colon delivery?
To prevent absorption and enable colonic release
Which characteristic is NOT an ideal property of an effective prodrug?
High toxicity compared to the drug
Why are carrier prodrugs designed for site specificity?
To transfer the drug to the specific site of action
What is a key reason for designing prodrugs for improved solubility?
Essential for parenteral dosage forms
How does a prodrug linked to a lipophilic carrier aid in brain drug delivery?
By crossing the blood-brain barrier efficiently
What is the purpose of designing prodrugs for colon delivery?
To release the drug in the colon by bacterial enzymes
Why does a prodrug have higher affinity for a specific site?
To enhance drug delivery to the target site
What does a prodrug linked to a polymer achieve in colon delivery?
It prevents absorption and allows colonic release.
Which is a common reason for designing prodrugs with a lipophilic carrier for brain delivery?
To facilitate crossing the blood-brain barrier and targeted release in the brain.
Which approach is commonly used for esters/amides to block the approach of nucleophile or enzyme?
Steric shields
What modification can be used to make drugs less resistant to metabolism?
Introducing metabolically susceptible groups
Which modification can reduce the metabolic susceptibility of drugs?
Ortho phenol of noradrenaline
For what purpose are prodrugs typically used?
To increase drug absorption
Which type of drug is given alongside analgesics for migraine to increase absorption?
'Sentry' drug
What is the major goal of modifying drugs to target exact locations?
Reduce side effects and toxicity
Which approach involves attaching drugs to important building blocks needed by rapidly dividing tumor cells?
'Targeting' drugs
'Chlorpropamide (X = Cl, n = 2)' was modified from which anti-diabetic drug?
'Tolbutamide (X = Me, n = 3)'
'Levodopa' is a prodrug for which neurotransmitter?
'Dopamine'
'A group that can't be important for binding can be masked temporarily in which type of modification?'
'Group shifts'
What is the key factor that influences a drug's solubility and ADME?
Optimizing hydrophilic/hydrophobic properties
Which type of drugs are preferentially distributed to hydrophobic compartments like the lipid bilayers of cells?
Hydrophobic drugs
Why are too polar/hydrophilic drugs unable to cross cell membranes effectively?
They cannot cross cell membranes due to their properties
What is the measure of a chemical substance's hydrophobic or hydrophilic nature?
Partition Coefficient (P)
Which strategy can help in improving a drug's absorption by increasing molecular flexibility?
Implementing a rigidification strategy
What type of modifications for polar groups can be used as bioisosteres?
-NH2 to -NHR or -NR2
Which type of substituents can be varied to alter a drug's pKa value?
-N-alkyl substituents
Why is it important to be cautious when changing substituents in drugs?
To ensure good binding properties are maintained
Which type of modifications can help improve a drug's efficacy by making it more resistant to hydrolysis?
-SO3H to -SO2R
What is the purpose of prodrugs like Lisdexamphetamine and Methyldopa?
To target specific areas within the body
Why are dipeptide analogues of Methyldopa preferred over Methyldopa?
They have increased intestinal absorption due to PepT1 transporter
What makes Lisdexamphetamine inactive prior to its absorption?
Essential amino acid L-lysine
How does Methyldopa act as an antihypertensive?
By inhibiting DOPA decarboxylase in the brain
How does Lisdexamphetamine become active after GI absorption?
By enzymatic cleavage by enzymes in red blood cells
What is a common feature of prodrugs like Prodrug Parecoxib, Nalbumetone, and Lisdexamphetamine?
They are all designed to avoid GI irritation
Which strategy is NOT mentioned for optimizing access to drug targets?
Eliminating drug toxicity by faster release
What role does the PepT1 transporter play in enhancing drug properties?
It enhances intestinal absorption of dipeptide analogues
Study Notes
Prodrugs and Optimizing Access to the Target
- A prodrug is a pharmacologically inactive compound that is metabolized to the active drug by chemical or enzymatic process.
- Prodrugs can be used to resolve issues of acid sensitivity, poor membrane permeability, toxicity, bad taste, short duration of action, etc.
- Bioprecursor prodrugs have the active drug already inside the structure, whereas carrier prodrugs are formed by combining an active drug with a carrier to form a compound with desired chemical and biological characteristics.
Design Strategies for Prodrugs
- Improve oral bioavailability
- Improve patient compliance
- Improve solubility
- Improve site specificity
- Improve resistance to chemical and enzymatic degradation
- Decrease resistance to drug metabolism
- Targeting drugs
- Drug alliances
- Endogenous compounds as drugs
Prodrug Design for Better Patient Acceptance
- Masking bitter taste or odor of the drug
- Improve solubility for parenteral dosage forms
- Use of palmitate ester in liquid formulations to mask bitter taste of chloramphenicol
Prodrug Design for Improved Solubility
- Use of disodium phosphate or hemi-succinate prodrugs to improve solubility
- Example: dexamethasone disodium phosphate
Prodrug Design for Site Specificity
- Design prodrugs that have a higher affinity for the specific site of action
- Use an enzyme that is mainly found at the target site to release the drug
- Example: brain delivery using dihydropyridine system
Prodrug Design for Brain Delivery
- Use a lipophilic carrier that distributes quickly in the body but eliminates quickly from other organs except the brain
- Use an enzyme that is mainly found in the brain to release the drug
Prodrug Design for Colon Delivery
- Link the active drug to a polymer to produce a prodrug that cannot be absorbed
- The drug is released in the colon by bacterial reductive enzyme
Resistance to Chemical and Enzymatic Degradation
- Use bioisosteres to stabilize labile functional groups
- Block susceptible positions
- Remove or replace susceptible metabolic groups
- Use fluoro substituent or H/D exchange
- Group shifts to move vulnerable groups
- Ring variation and ring substituents
- Introduce metabolically susceptible groups to reduce toxicity
Targeting Drugs
- Use targeting strategies to deliver the drug to the specific site of action
- Examples: tumor cells, gastrointestinal infections, peripheral regions, and nervous system
Drug Alliances
- Use a second drug to guard or assist the principal drug
- Examples: metaclopromide with analgesics for migraine, adrenaline with procaine for localized anesthesia
Endogenous Compounds as Drugs
- Natural hormones as drugs
- Peptides and proteins as drugs
- Oligonucleotides as drugs
- Antibodies as drugs
Join Dr. A. Edwards, Senior Lecturer in Pharmaceutical Chemistry at Medway School of Pharmacy, as he covers the topic of Prodrugs and Optimising Access to the Target in this lecture. Recommended reading includes 'An introduction to medicinal chemistry' by Graham Patrick.
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