EXAM 3 - Chemical Methods for Improving Pharmacokinetics

Question 1

Explain the importance of optimizing pharmacokinetics.

Answer 1

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

Question 2

What is the relationship between optimizing pharmacokinetics and optimizing biological activity?

Answer 2

Optimization of biological activity and pharmacokinetics occurs at the same time (NOT sequential)

Question 3

Why are bioisoteres used for PK optimization?

Answer 3

• 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

Question 4

What are the 3 main parameters for optimizing PK?

Answer 4

Hydrophilic/hydrophobic properties
* solubility, intestinal absorption
* binding site interactions

Resistance to degradation
* metabolic stability

Prodrugs - inactive –> active
* solubility, intestinal absorption

Question 5

Explain the importance of the hydrophobicity and hydrophilicity balance.

Answer 5

• 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

Question 6

What is the first choice modification of H-philic/phobic properties?

Answer 6

First choice - addition/removal of FGs NOT essential for binding
* remember: adding FGs increases MW/size

Question 7

What is the second choice of modifying H-philic/phobic properties?

Answer 7

Second choice - modify FGs essential for binding
* retention of biological activity is key!
* bioisotere replacement is common

Question 8

Explain the substituent hydrophobicity constant (pi).

Answer 8

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

Question 9

Explain the meaning of logP

Answer 9

LogP - quantifiable value for hydrophobic character of a drug
P= [drug(organic)]/[drug(aqueous)]
* logP < 5 –> improved oral bioavailability

Question 10

How do peptidases and esterases contribute to metabolic stability?

Answer 10

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.

Question 11

How do CYP450 contribute to metabolic stability?

Answer 11

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

Question 12

What are the two main sites for aromatic metabolism by CYP450?

Answer 12

Methyl on an aromatic ring –> gets replaced with bioisostere (Cl)

Aromatic ring with hydrogen on para position –> replaced with bioisostere (F)

Question 13

Answer 13

Question 14

Answer 14

B. An inactive precursor that relies on natural mechanisms to be converted to the active drug form.

Question 15

Define a prodrug.

Answer 15

Substance that is administered in an inactive form and then relies on natural mechanisms (usually metabolsim) for conversion to the active drug.

Question 16

What are some reasons for use of prodrugs?

Answer 16

• acid sensitivity
• membrane permeability (oral bioavailability)
• minimize toxicity
• short duration of action
• target drug to specific tissue

Question 17

Describe considerations of prodrugs.

Answer 17

• 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)

Question 18

Explain the two prodrug classes and their subgroups.

Answer 18

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

Question 19

Explain the significance of esters as prodrugs.

Answer 19

Esters are rapidly cleaved –> convert inactive precursor to active drug
* can enhance membrane permeability of easily ionizable carboxylic acid

Question 20

Explain what affects the rate of ester cleavage.

Answer 20

Electronegativity
* electron donating group –> slower duration/release of active form (CH3)
* electron withdrawing group –> wants to be cleaved more rapidly - faster conversion (F)

Question 21

How/why do prodrugs (Acyclovir) work to target a specific tissue.

Answer 21

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.

Question 22

How does omeprazole function as a prodrug (that targets specific tissue)?

Answer 22

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

Question 23

Describe antibody drug conjugate prodrugs.

Answer 23

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

Question 24

Answer 24

A. Type 1A