4-substituted 2-alkoxytetrahydrofurans as potent and long-lasting PAF antagonists

J Med Chem. 1992 Feb 21;35(4):676-83. doi: 10.1021/jm00082a007.

Abstract

A series of 4-substituted 2-alkoxytetrahydrofuran derivatives featuring an acetal group were prepared and evaluated for PAF antagonist activity in the PAF-induced in vitro platelet-aggregation and in vivo hypotension tests. Compound 2-[[N-acetyl-N-[[[2-(octadecyloxy)tetrahydrofuran-4- yl]methoxy]carbonyl]amino]methyl]-1-ethylpyridinium chloride (4e, UR-11353) was selected for further development on the basis of its high activity and long-lasting action. The compound maintained a significant activity even 24 h after administration of a single dose of 1 mg/kg iv in the PAF-induced mortality test in mice and 10 h after administration of the same dose in the PAF-induced hypotension test in rats. Comparison with previously reported carba analogues suggests that the presence of the acetal group is the structural characteristic that confers its long-lasting activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Furans / chemistry*
  • Furans / pharmacology*
  • Hypotension / chemically induced
  • Hypotension / prevention & control
  • Male
  • Mice
  • Molecular Structure
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Activating Factor / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemistry*
  • Platelet Aggregation Inhibitors / pharmacology
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / pharmacology*
  • Rabbits
  • Rats
  • Rats, Inbred Strains

Substances

  • Furans
  • Platelet Activating Factor
  • Platelet Aggregation Inhibitors
  • Pyridinium Compounds
  • UR 11353
  • tetrahydrofuran