Chapter 16 Plasma stability 2014. 1.10. Lee, Sang-Hwi

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.

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.

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.

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

12.1 Plasma Stability Fundamentals

12.1 Plasma Stability Fundamentals

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.

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.

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

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.

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

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.

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

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

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