1. Chapter 16
Plasma stability
Lee, Sang-Hwi

2. Overview
Compound decomposition can be catalyzed in plasma by hydrolytic enzymes.
Increased clearance can occur for hydrolyzable substrate compounds.
Plasma stability increases with
Steric hindrance
Electron-withdrawing groups
Replacement with a less reactive group.

3. 12.1 Plasma Stability Fundamentals
Hydrolytic enzymes in Blood contains
Cholinesterase
Aldolase
Lipase
Dehydropeptidase(DPEP)
Alkaline and phosphatase
The amount of each enzyme is dependent on species, disease state, gender, age, and race.
If the compound has affinity for one of these enzymes and it has a hydrolyzable group in the right position, it can be decomposed in the plasma.

4. Susceptible Functional groups to plasma degradation Ester Amide
Carbamate
Lactam
Lactone
Sulfonamide
Leads containing these groups, especially peptides and peptide mimetics, should be tested for plasma stability.

5. 12.1 Plasma Stability Fundamentals
Consequences of Chirality on Plasma Stability
Chirality 따라 stability도 차이가 있음.
Propranolol
: β-blocker(고혈압, 협심증 치료제)

6. 12.1 Plasma Stability Fundamentals

7. 12.1 Plasma Stability Fundamentals

8. 12.2 Effects of Plasma Stability
Prodrug
enhances permeability or metabolic stability so that high concentrations of the prodrug reach the bloodstream.
Antedrugs (soft drug)
the opposite of prodrugs.
These drugs are active locally but rapidly degrade to an inactive compound once they reach the bloodstream.
The purpose of this action is to reduce side effects by minimizing the systemic toxicity of the drug.

9. 12.2 Effects of Plasma Stability
Antedrugs(“soft drug”)
The inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGFl ike growth factor
Target disease : psoriasis (inflammatory skin disease)
Also inhibited matrix metallo proteinases (MMPs).
Introduce the antedrug concept.

10. 12.2 Effects of Plasma Stability (Antedrugs : soft drug)
Ciclesonide : lung diseases (asthma and chronic obstructive pulmonary disease)
Fluocortin–butyl : Topical anti-inflammatory agent
The gain in therapeutic benefit is limited because of low intrinsic activity
An ester soft drug of the inactive metabolite of fluocortolon.
Fluocortolone
Loteprednol Etabonate : eye inflammation.
An ester soft drug of the inactive metabolite cortienic acid

11. 12.2 Effects of Plasma Stability
Plasma stability can vary greatly among species
rat < dog < human
Typically, compounds are less stable in rodents than in humans.
The CNS-penetrant Human NK(neurokinin)-1 receptor antagonist.

12. 12.2 Effects of Plasma Stability
Ester prodrug of an a-glucosidase 1 inhibitor
Reduces replication of the human immune deficienc virus(HIV).

13. 12.3 Structure modification strategies to improve Plasma stability
Substitute an Amide for an Ester
PKB-α : Protein kinase B
PKA : protein kinase A
PKB is located downstream in the PI-3 kinase
drugs for cancer therapy as effective sensitizers or inducers of apoptosis.

14. 12.3 Structure modification strategies to improve plasma Stability
Increase steric hindrance
serine protease inhibitors
HCMV antiviral activity : human cytomegalovirus

15. 12.3 Structure Modification Strategies to Improve Plasma Stability
Add electron-withdrawing groups to decrease Plasma Stability for Antedrug

16. 12.4 Applications of Plasma Stability Data
Diagnose Poor In Vivo Performance
Alert Teams to a Liability
Prioritize Compounds for In Vivo Animal Studies
Prioritize Synthetic Efforts
Screening of Prodrugs
Guide Structural Modification