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Related Experiment Videos

Azole endothelin antagonists. 3. Using delta log P as a tool to improve absorption

T W von Geldern1, D J Hoffman, J A Kester

  • 1Aging and Degenerative Diseases Research, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.

Journal of Medicinal Chemistry
|February 16, 1996
PubMed
Summary

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Researchers improved oral absorption of ET(A) antagonists by modifying drug structures. Analyzing physicochemical properties like delta log P helped reduce hydrogen bonding, enhancing drug potency and bioavailability for potential oral administration.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Endothelin receptor type A (ET(A)) antagonists are investigated for therapeutic applications.
  • Optimizing oral absorption is crucial for developing effective drug candidates.
  • Physicochemical properties significantly influence a drug's pharmacokinetic profile.

Purpose of the Study:

  • To enhance the oral absorption of azole-based ET(A)-selective antagonists.
  • To identify structural modifications that improve both drug potency and bioavailability.
  • To establish a correlation between physicochemical parameters and absorption characteristics.

Main Methods:

  • Utilized delta log P analysis to assess physicochemical properties of drug candidates.
  • Performed structural modifications on urea-based compounds to reduce solvent hydrogen-bonding capacity.

Related Experiment Videos

  • Evaluated drug absorption using an intraduodenal (id) bioavailability model.
  • Assessed receptor affinity and selectivity for ET(A).

    • Main Results:

    • Delta log P analysis indicated that compound 2 had excessive hydrogen-bonding capacity.
    • Structural modifications successfully reduced hydrogen-bonding capacity while maintaining ET(A) receptor affinity.
    • A strong correlation was observed between delta log P values and intraduodenal absorption.
    • Optimized modifications led to carbamate 16h, a potent and selective ET(A) antagonist.
    • Carbamate 16h demonstrated a favorable potency/bioavailability profile for oral administration.

    Conclusions:

    • Rational structural modification guided by delta log P analysis is effective for improving oral absorption of ET(A) antagonists.
    • Reducing hydrogen-bonding capacity is a viable strategy to enhance drug bioavailability.
    • The developed carbamate 16h represents a promising candidate for oral ET(A) antagonist therapy.