In vitro and in vivo activities of the novel antiplatelet agent alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide.
In an effort to develop compounds with high antithrombotic activity and minimal toxicity, our laboratory has synthesized a number of nipecotamides. The effectiveness of one of these compounds, alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (A-1), in inhibiting both in vitro and in vivo platelet aggregation is reported here, along with its acute toxicity. The IC50 of A-1 in in vitro ADP- and PAF-induced platelet aggregation was 44.5 microM and 21.2 microM, respectively. Suppression of intraplatelet [Ca2+] is suggested as a likely mediator of the aggregation-inhibitory properties of A-1, since both the release of cytosolic Ca2+ and the influx of extracellular Ca2+ were decreased. The ED50 of A-1 in protecting mice against thromboembolism induced by a collagen-epinephrine challenge was 164 mumol/kg. The measurement of the acute toxicity of this compound as the LD50 was 691 mumol/kg, with the therapeutic index being 4.2. These data indicate that compounds in this family hold promise as clinically effective antithrombotic agents.
Lyman
B A
BA
Department of Medicinal Chemistry, University of Tennessee-Memphis 38163.
Bond
S E
SE
Dillingham
E O
EO
Lawrence
W H
WH
Gollamudi
R
R
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000097:blood; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009557:Nipecotic Acids / Q000494:pharmacology* / Q000633:toxicity; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000633:toxicity
D005343:Fibrinolytic Agents; D009557:Nipecotic Acids; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; C043099:alpha, alpha'-bis(3-(N,N-diethylcarbamoyl)piperidino)-4-xylene; D000244:Adenosine Diphosphate; D002118:Calcium