(+/-)-trans-2-(3-Methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist.
The title compound, L-659,989, is a highly potent, competitive, and selective antagonist of the binding of [3H]PAF to its receptors in platelet membranes from rabbits and humans. It exhibits equilibrium inhibition constants for PAF binding of 1.1 nM (rabbit) to 9.0 nM (human), values that are at least 1-2 orders of magnitude lower than those of other PAF antagonists tested. L-659,989 potently inhibits PAF-induced aggregation of rabbit platelets and degranulation of rat (ED50 4.5 nM) and human (ED50 10 nM) neutrophils. L-659,989 inhibits PAF-induced extravasation and lysosomal enzyme release in rats, and is active orally in female rats (ED50 0.2 mg/kg) with an extraordinary oral duration of action of 12 to 16 hours at 1.0 mg/kg p.o.
Ponpipom
M M
MM
Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
Hwang
S B
SB
Doebber
T W
TW
Acton
J J
JJ
Alberts
A W
AW
Biftu
T
T
Brooker
D R
DR
Bugianesi
R L
RL
Chabala
J C
JC
Gamble
N L
NL
D000118:Acetylglucosaminidase / Q000097:blood; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006168:Guinea Pigs; D006400:Hematocrit; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled
D005663:Furans; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C054893:L 659989; D000118:Acetylglucosaminidase