Plasma stability

2014. 1.10.Lee, Sang-Hwi

Chapter 16

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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.

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12.1 Plasma Stability Fundamentals

Hydrolytic enzymes in Blood contains

① Cholinesterase② Aldolase ③ Lipase ④ Dehydropeptidase(DPEP) ⑤ 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 ① Ester ② Amide③ Carbamate④ Lactam⑤ Lactone⑥ Sulfonamide

• Leads containing these groups, especially peptides and peptide mimetics, should be tested for plasma stability.

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12.1 Plasma Stability Fundamentals

• Consequences of Chirality on Plasma Stability• Chirality 따라 stability 도 차이가 있음 .

Propranolol: β-blocker( 고혈압 , 협심증 치료제 )

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12.1 Plasma Stability Fundamentals

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12.1 Plasma Stability Fundamentals

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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.

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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.

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12.2 Effects of Plasma Stability (Antedrugs : soft drug)

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.

Loteprednol Etabonate : eye inflammation. An ester soft drug of the inactive metabolite cortienic acid

Ciclesonide : lung diseases (asthma and chronic obstructive pulmonary disease)

Fluocortolone

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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.

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12.2 Effects of Plasma Stability

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

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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.

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12.3 Structure modification strategies to improve plasma Stability

• Increase steric hindrance

• serine protease inhibitors• HCMV antiviral activity : human cytomegalovirus

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12.3 Structure Modification Strategies to Improve Plasma Stability

• Add electron-withdrawing groups to decrease Plasma Stability for Antedrug

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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