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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