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.
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