Transcript 12.2 Effects of Plasma Stability

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.
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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
②
③
④
⑤
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.
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• Susceptible Functional groups to plasma degradation
① Ester
② Amide
③ Carbamate
④ Lactam
⑤ Lactone
⑥ Sulfonamide
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Leads containing these groups, especially peptides and peptide mimetics, should
be tested for plasma stability.
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12.1 Plasma Stability Fundamentals
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Consequences of Chirality on Plasma Stability
Chirality 따라 stability도 차이가 있음.
Propranolol
: β-blocker(고혈압, 협심증 치료제)
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)
 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
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12.2 Effects of Plasma Stability
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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 aglucosidase 1 inhibitor
- Reduces replication of the
human immune deficienc
virus(HIV).
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12.3 Structure modification strategies
to improve Plasma stability
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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
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serine protease inhibitors
HCMV antiviral activity : human cytomegalovirus
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12.3 Structure Modification Strategies to
Improve Plasma Stability
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Add electron-withdrawing groups to decrease Plasma Stability for
Antedrug
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12.4 Applications of Plasma Stability Data
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Diagnose Poor In Vivo Performance
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Alert Teams to a Liability
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Prioritize Compounds for In Vivo Animal Studies
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Prioritize Synthetic Efforts
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Screening of Prodrugs
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Guide Structural Modification
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Plasma stability assay
Use our plasma stability assay to measure the degradation of compounds in plasma
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