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Azole endothelin antagonists. 2. Structure-activity studies

T W von Geldern1, J A Kester, R Bal

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

Journal of Medicinal Chemistry
|February 16, 1996
PubMed
Summary
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Researchers enhanced novel azole-based endothelin-A (ETA) antagonists by modifying urea groups and N-methylation. These structural changes significantly boosted receptor affinity and potency, yielding highly active compounds.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology

Background:

  • Endothelin-A (ETA) receptor antagonists are investigated for therapeutic potential.
  • Novel azole-based compounds were synthesized as potential ETA antagonists.

Purpose of the Study:

  • To improve the potency and receptor affinity of novel azole-based endothelin-A (ETA) selective antagonists.
  • To explore structure-activity relationships (SAR) through chemical modifications.

Main Methods:

  • Systematic modifications of the hydrophobic group on the terminal urea moiety.
  • Incorporation of cyclohexyl or aryl ureas.
  • Conformational restriction of specific chemical groups.
  • N-methylation of the indole moiety within the heterocyclic dipeptide surrogate.

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Main Results:

  • Modifications to the hydrophobic urea group significantly impacted receptor affinity.
  • Cyclohexyl and aryl urea substitutions led to substantial increases in antagonist activity.
  • Conformational restriction further enhanced the beneficial effects.
  • N-methylation of the indole moiety also improved potency.
  • Synergistic effects were observed between urea modification and N-methylation.
  • The most potent analogs (e.g., 14q, 15y, 15ff) showed an 80-200 fold improvement in activity.

Conclusions:

  • Strategic modifications of azole-based scaffolds can significantly enhance ETA antagonist potency.
  • Combined modifications, specifically urea group alteration and N-methylation, yield synergistic improvements.
  • Optimized analogs demonstrate considerable potential as therapeutic agents targeting ETA receptors.