EXAM 3 - Chemical Methods for Improving Pharmacokinetics Flashcards
Explain the importance of optimizing pharmacokinetics.
Pharamcokinetics studies the concerns with evaluating what changes the body makes on a given drug.
* key: retain binding affinity and biological activity while improving parameters that allow drug to reach the target
* aqueous solubility, chemical and metabolic stability, and intestinal absorption
What is the relationship between optimizing pharmacokinetics and optimizing biological activity?
Optimization of biological activity and pharmacokinetics occurs at the same time (NOT sequential)
Why are bioisoteres used for PK optimization?
- used to replace functional groups that are important for binding but have other detrimental properties
- used to replace groups unimportant to binding in the auxophore
–> to improve PK properties
What are the 3 main parameters for optimizing PK?
Hydrophilic/hydrophobic properties
* solubility, intestinal absorption
* binding site interactions
Resistance to degradation
* metabolic stability
Prodrugs - inactive –> active
* solubility, intestinal absorption
Explain the importance of the hydrophobicity and hydrophilicity balance.
- Small molecule binding sites on protein targets are typically hydrophobic
- Drugs must be hydrophilic to be orally bioavailable
- Passive diffusion through the membrane is only possible for uncharged molecules
Small molecule drugs must maintain balance between hydrophobic properties needed to bind to their target and the hydrophilic properties they need to be a drug
What is the first choice modification of H-philic/phobic properties?
First choice - addition/removal of FGs NOT essential for binding
* remember: adding FGs increases MW/size
What is the second choice of modifying H-philic/phobic properties?
Second choice - modify FGs essential for binding
* retention of biological activity is key!
* bioisotere replacement is common
Explain the substituent hydrophobicity constant (pi).
Contribution of a given FG to hydrophobicity relative to hydrogen.
* high pi - increased hydrophobicity and decreased water solubility
* low pi - decreased hydrophobity and increased water solubility
pi - predicts FG contribution to logP
Explain the meaning of logP
LogP - quantifiable value for hydrophobic character of a drug
P= [drug(organic)]/[drug(aqueous)]
* logP < 5 –> improved oral bioavailability
How do peptidases and esterases contribute to metabolic stability?
Peptidases and esterases metabolize esters and peptides rapidly
* drugs that have esters/peptides will have very short half life (not good)
To counter the rapid metabolism of esters/peptides, you can add bond mimics, bioisoteres, and steric shields to block their metabolism.
How do CYP450 contribute to metabolic stability?
Responsible for general metabolism
two steps:
* Oxidation - adds carboxylic acid/hydroxyl that it is trying to metabolize
* Conjugation - add something large to make more hydrophilic
Increases water solubility
What are the two main sites for aromatic metabolism by CYP450?
Methyl on an aromatic ring –> gets replaced with bioisostere (Cl)
Aromatic ring with hydrogen on para position –> replaced with bioisostere (F)
B. An inactive precursor that relies on natural mechanisms to be converted to the active drug form.
Define a prodrug.
Substance that is administered in an inactive form and then relies on natural mechanisms (usually metabolsim) for conversion to the active drug.
What are some reasons for use of prodrugs?
- acid sensitivity
- membrane permeability (oral bioavailability)
- minimize toxicity
- short duration of action
- target drug to specific tissue
Describe considerations of prodrugs.
- Prodrug must be converted without production of toxic groups
- Kinetics of biotransformation is crucial (metabolized/released at the desired rate)
- Chemistry involved should be simple
- Prodrug might get you new intellectual property (extend patent life)
Explain the two prodrug classes and their subgroups.
Think about where it is converted!
Type 1 - converted to its active form inside cell
* 1A - conversion in therapeutic target tissue
* 1B - conversion in metabolic tissue (liver/lungs)
* Can be 1A and 1B if the target tissue is liver or lungs
Type 2 - converted to active form outside cell
* 2A - conversion in the GI fluid (stomach)
* 2B - conversion in the systemic circulation
Explain the significance of esters as prodrugs.
Esters are rapidly cleaved –> convert inactive precursor to active drug
* can enhance membrane permeability of easily ionizable carboxylic acid
Explain what affects the rate of ester cleavage.
Electronegativity
* electron donating group –> slower duration/release of active form (CH3)
* electron withdrawing group –> wants to be cleaved more rapidly - faster conversion (F)
How/why do prodrugs (Acyclovir) work to target a specific tissue.
Acyclovir - antiviral; inhibits DNA replication
* Human thymidine kinases cannot convert acyclovir to monophosphate –> BUT viral thymidine kinases can add the intial phosphate!
* Cells not infected by virus (and lack viral thymidine kinase) cannot activate drug.
How does omeprazole function as a prodrug (that targets specific tissue)?
Omeprazole is a weak base that is uncharged at physiological pH.
* selectively accumulates in parietal cells (stomach cells that secrete HCl)
* unstable in acidic environment –> converts to active compound
Describe antibody drug conjugate prodrugs.
Specifically target small molecule to release and convert to active form in target cell.
* ADCs use antibody covalently linked to a small molecule
* the small molecule is very toxic and cannot be freely circulating
* Antibody targets a specific receptor on the surface of the target cell –> ADC-receptor complex is internalized (enters cell)
* complex is degraded and releases cytotoxin –> cytotoxin binds to the target
* result: apoptosis
A. Type 1A
