MK 287: a potent, specific, and orally active receptor antagonist of platelet-activating factor.
MK 287 (L-680,573), a tetrahydrofuran analog, potently inhibited [3H]C18-PAF binding to human platelet, polymorphonuclear leukocyte (PMN) and lung membranes with K1 values of 6.1 +/- 1.5, 3.2 +/- 0.7, and 5.49 +/- 2.3 nM, respectively. The inhibitory effects are stereospecific and competitive. The racemate, L-668,750 is less potent and the enantiomer, L-680,574 is 20-fold less potent than MK 287. Inhibition of the binding of [3H]C18-PAF to human PMN membranes by MK 287 was associated with the reduction of the affinity of the radioligand but not the number of the receptor sites. Binding of other radioligands (e.g., LTB4, LTC4, C5a, FMLP) to their specific receptors was unaltered at 1-10 microM MK 287. [3H]MK 287 bound to membranes from human platelets and PMNs: KD = 2.1 +/- 0.6 and 2.9 +/- 1.2 nM, respectively. When examined on isolated human cells, MK 287 potently and selectively inhibited PAF-induced aggregation of platelets in plasma (ED50 = 56 +/- 38 nM) or gel-filtered platelets (ED50 = 1.5 +/- 0.5 nM) and elastase release from PMNs (ED50 = 4.4 +/- 2.6 nM). In studies in vivo, MK 287 inhibited PAF-induced lethality in mice (ED50 = 0.8 mg/kg orally) and PAF-induced bronchoconstriction in guinea pigs (ED50 = 0.18 mg/kg intraduodenally and 0.19 mg/kg intravenously). Inhibition of PAF-induced bronchoconstriction was accompanied by parallel rightward shifts in concentration-response curves for PAF-induced platelet aggregation measured ex vivo.
Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
S B
SB
Hwang
M H
MH
Lam
D M
DM
Szalkowski
D E
DE
MacIntyre
T J
TJ
Bach
S
S
Luell
R
R
Meuer
S P
SP
Sahoo
A W
AW
Alberts
J C
JC
Chabala
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012680:Sensitivity and Specificity; D014316:Tritium
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; D014316:Tritium; C071469:MK 287