Pharmacologic activity of bepafant (WEB 2170), a new and selective hetrazepinoic antagonist of platelet activating factor.
The hetrazepine WEB 2170 (international nonproprietary name: bepafant), a thieno-triazolodiazepine that is structurally related to the recently described platelet activating factor (PAF) antagonist WEB 2086, is a potent and selective PAF antagonist both in vitro and in vivo. WEB 2170 inhibited PAF-induced human platelet and neutrophil aggregation in vitro (IC50 values: 0.3 and 0.83 microM, respectively) but had little or no inhibitory action against aggregation induced by other agonists. The potency in vitro was comparable to that described recently for WEB 2086 (Casals-Stenzel, J., Muacevic, G. and Weber, K.H.: J. Pharmacol. Exp. Ther. 241: 974-981, 1987). When guinea pigs were given i.v. infusions of PAF at 30 ng x kg-1 x min-1, oral (0.005-0.5 mg/kg) as well as intravenous (0.005-0.05 mg/kg) treatment with WEB 2170 abrogated the intrathoracic accumulation of 111In-labeled platelets, the bronchoconstriction and the hypotension as well as the finally occurring death in a dose-dependent fashion. Oral (0.01-1 mg/kg) and intravenous (0.005-0.1 mg/kg) WEB 2170 shared with the beta 2 agonist fenoterol and the steroid dexamethasone the property of protecting elderly NMRI mice from the lethal effect of PAF. In anesthetized rats, intravenous (0.001-0.1 mg/kg) and oral (0.05-1 mg/kg) WEB 2170 inhibited PAF-induced hypotension in a dose-related manner. Coadministration of WEB 2170 inhibited PAF-induced increase of vascular permeability in rat skin very effectively. The half-time of duration of action in the rat was estimated to be about 5 to 6 h after oral administration and about 1.1 to 2.3 h after intravenous application. In conclusion, the hetrazepine WEB 2170 is a strong and selective PAF antagonist, which is in vitro more or less equipotent to WEB 2086. In contrast, in vivo oral WEB 2170 is--depending on the species and considered parameter--about 5 to 40 times more potent against exogenous PAF-induced alterations than the recently described hetrazepine WEB 2086. Particularly in mice and rats, oral WEB 2170 is by far superior to WEB 2086.
Heuer
H O
HO
Department of Pharmacology, Boehringer Ingelheim KG, Ingelhelm/Rh., Germany.
Casals-Stenzel
J
J
Muacevic
G
G
Weber
K H
KH
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D007262:Infusions, Intravenous; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C063964:bepafant