4-substituted 2-alkoxytetrahydrofurans as potent and long-lasting PAF antagonists.
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.
Carceller
E
E
Laboratory of Chemistry, Research Center, J. Uriach & Cía.S.A., Barcelona, Spain.
Merlos
M
M
Giral
M
M
Bartrolí
J
J
García-Rafanell
J
J
Forn
J
J
D000818:Animals; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D005663:Furans; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; C073186:UR 11353; C018674:tetrahydrofuran