Biochemical and pharmacological activities of SR 27417, a highly potent, long-acting platelet-activating factor receptor antagonist.
SR 27417 [N-(2-dimethylamino ethyl)-N-(3-pyridinyl methyl)[4- (2,4,6-triisopropylphenyl) thiazol-2-yl]amine] is the first member of a newly developed platelet-activating factor (PAF) antagonist series. It is a highly potent, competitive and selective antagonist of the binding of [3H]PAF to its receptor in rabbit platelets. It exhibits an equilibrium inhibition constant for PAF binding of 57 pM, a value that is at least 5-fold lower than that of unlabeled PAF itself. SR 27417 potently inhibited PAF-induced aggregation of rabbit and human platelets in vitro (IC50 = 0.10 and 0.50 nM, respectively) but had no effect on the action of other platelet-aggregating agents. In comparison with the triazolothienodiazepine WEB-2086, SR 27417 was 470 and 70 times more potent against PAF-induced aggregation of rabbit and human platelets, respectively. SR 27417 displayed marked in vitro inhibition of PAF-induced oxidative burst in guinea pig macrophages (IC50 = 32 nM). In an in vivo model, it protected mice from 100 micrograms/kg PAF-induced death when given i.v. (ED50 = 7.5 micrograms/kg) 5 min before PAF challenge or p.o. (ED50 = 45 micrograms/kg) 3 hr before PAF administration. SR 27417 inhibited PAF-induced death in mice with an impressive p.o. or i.v. duration of action of 30 to 48 hr. In anesthetized guinea pigs, SR 27417 inhibited i.v. and p.o. 100 ng/kg PAF-induced bronchoconstriction (ED50 = 14 and 140 micrograms/kg, respectively), hemoconcentration (ED50 = 20 and 270 micrograms/kg, respectively), thrombocytopenia (ED50 = 30 and 240 micrograms/kg, respectively) and leukopenia (ED50 = 0.1 and 1.5 mg/kg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Herbert
J M
JM
Sanofi Recherche, Toulouse, France.
Bernat
A
A
Valette
G
G
Gigo
V
V
Lale
A
A
LaPlace
M C
MC
Lespy
L
L
Savi
P
P
Maffrand
J P
JP
Le Fur
G
G
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007275:Injections, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D051379:Mice; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; C071317:Foropafant