Some novel inhibitors of platelet aggregation: acute toxicity in mice and its relationship to in vitro efficacy and toxicity. II. Nipecotoylaminoalkane and nipecotoylpiperazine congeners.
Four closely related nipecotoyl congeners are employed as molecular probes to evaluate the effects of systematic molecular changes upon lethal potency of the compounds. The in vivo toxicities, effected by changes in molecular structure, are compared to their in vitro concentrations inhibiting ADP-induced aggregation and epinephrine-induced primary aggregation of human blood platelets and their toxicities to mouse fibroblasts (L-929 cells) in culture. To assist in the selection of compounds which offer the greatest promise as therapeutic agents for further evaluation and to guide future development of optimal molecular structures, a ratio of acute ip LD50 (mumol/kg) [Tm] to concentration inhibiting 50% ADP-induced platelet aggregation (mumol/liter) [A] is calculated for each compound. These ratios range from 2.41 to 24.92 for the four compounds included in this study.
Lawrence
W H
WH
Department of Medicinal Chemistry, College of Pharmacy, University of Tennessee, Memphis 38163.
Lasslo
A
A
Turner
J E
JE
Feng
Z
Z
Bond
S E
SE
D000473:Alkanes / Q000633:toxicity*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002478:Cells, Cultured; D004837:Epinephrine / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009557:Nipecotic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000633:toxicity*; D010975:Platelet Aggregation Inhibitors / Q000633:toxicity*
D000473:Alkanes; D009557:Nipecotic Acids; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D004837:Epinephrine