Synthesis and structure-activity relationships of a series of novel benzopyran-containing platelet activating factor antagonists.
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.
Guinn
D E
DE
Immunosciences Research Area, Abbott Laboratories, Abbott Park, Illinois 60064.
Summers
J B
JB
Heyman
H R
HR
Conway
R G
RG
Rhein
D A
DA
Albert
D H
DH
Magoc
T
T
Carter
G W
GW
D000478:Alkylation; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D012769:Shock / Q000139:chemically induced; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D001643:Bridged Bicyclo Compounds; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C074916:10-((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