Synthesis and Structure-Activity Relationships of a Series of Novel Benzopyran-Containing Platelet Activating Factor Antagonists

J Med Chem. 1992 May 29;35(11):2055-61. doi: 10.1021/jm00089a016.

Abstract

A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little effect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and O-substituents resulted in the analogues 25-27 which exhibited Ki values ranging between 131 and 167 nM in a [3H]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.

Publication types

  • Comparative Study

MeSH terms

  • Alkylation
  • Animals
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / metabolism
  • Benzopyrans / pharmacology
  • Binding Sites
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Blood Platelets / ultrastructure
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacology
  • Cell Membrane / metabolism
  • Cytoplasmic Granules / drug effects
  • Male
  • Mice
  • Molecular Structure
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Activating Factor / metabolism
  • Platelet Activating Factor / pharmacology
  • Platelet Membrane Glycoproteins*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Rabbits
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled*
  • Shock / chemically induced
  • Structure-Activity Relationship

Substances

  • Benzopyrans
  • Bridged Bicyclo Compounds
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Pyridines
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • 10-((ethoxycarbonyl)methoxy)-8-(4-(4-fluorophenyl)-1-methylbutyl)-1,2,3,4-tetrahydro-N,5,5-trimethyl-5H-(1)-benzopyrano(4,3-c)pyridine-2-acetamide