Download 12.1 Plasma Stability Fundamentals

Plasma stability
12.1 Plasma Stability Fundamentals
Blood contains hydrolytic enzymes.
(cholinesterase, aldolase, lipase, dehydropeptidase,
alkaline, acid phosphatase)
Compound decomposition can be catalyzed in
plasma by hydrolytic enzymes.
12.1 Plasma Stability Fundamentals
 If the compound has affinity for these
enzymes and it has a hydrolyzable group, it
can be decomposed in the plasma.
-
Ester
Amide
Carbamate
Lactam
Increased clearance
Lactone
Sulfonamide
peptides and Peptide mimetics
12.1.1 Consequences of Chirality on
Plasma Stability
 Plasma stability is affected by chirality, owing to
differential binding of enantiomers to plasma enzymes.
12.2 Effect of Plasma Stability
 In the blood, a hydrolytic enzyme cleaves the
prodrug to release the active drug.
 Antedrugs (soft- drugs)
- the opposite prodrugs
- active locally but rapidly degrade to an inactive
compound once they reach the bloodstream
- To reduce side effects by minimizing the systemic
toxicity of the drug
12.2 Effect of Plasma Stability
12.2 Effect of Plasma Stability
 The plasma stability of compound increased order
: rat < dog < human
12.3 Structure Modification Strategies
to improve Plasma Stability
12.3.1 Substitute an amide for an Ester
 Amides are more stable against plasma hydrolysis.
12.3.2 Increase Steric Hindrance
 Addition of steric hindrance near a hydrolyzable
group can increase plasma stability.
12.3.2 Increase Steric Hindrance
 Addition of steric hindrance near a hydrolyzable
group can increase plasma stability.
12.3.3 Electron-withdrawing Groups
Decrease Plasma Stability for Antedrug
 Including EWG increased the positive charge on the
phosphorous atom and increased the rate of hydrolysis
12.4 Applications of Plasma stability
Data
① Diagnose Poor In Vivo Performance
② Alert Teams to a Liability
③ Prioritize Compounds for In Vivo Animal studies
12.4 Applications of Plasma stability
Data
④ Prioritize Synthetic Efforts
12.4 Applications of Plasma stability
Data
⑤ Screening of Prodrugs
12.4 Applications of Plasma stability
Data
⑥ Guide Structural Modification
Problems
1. Which of the following structures might be partially or
completely unstable in plasma?
Problems
2. List two applications where plasma instability is
advantageous.
- Prodrugs, Antedrugs
Problems
3. What are some structural modifications that you could
try in order to improve the plasma stability of the
following compound?
Problems
4. Microsomes have hydrolysis activity. Are they useful for
assessing potential plasma hydrolysis?
- No. The hydrolysis enzymes in microsomes and plasma
are different and should be assessed separately.
5. Which of the following groups should alert you to
potential degradation due to plasma hydrolysis? :
(a) phenyl, (b) carboxylic acid, (c) ester, (d) lactone, (e)
trifluoromethyl, (f) carbamate, (g) amide