Some novel inhibitors of platelet aggregation: acute toxicity in mice and its relationship to in vitro activity and toxicity.

Five carbamoylpiperidine congeners and one nipecotoylpiperazine derivative, which inhibit ADP-induced aggregation of human blood platelets in vitro, were evaluated in vivo for acute toxicity to male and female ICR mice. Although the in vitro platelet aggregation inhibiting potency of these compounds covered about a 1150-fold range, the acute ip LD50s (microM/kg) in mice showed only a fourfold range of values. An increase in platelet aggregation inhibiting potency (in vitro) was not paralleled by an increase in acute toxicity in vivo for these compounds; in fact, the most potent aggregation inhibitor (microM/liter) was the least toxic (microM/kg) to mice. A comparison of acute LD50s (microM/kg) to concentrations which produce 50% inhibition of mouse fibroblast cell growth in culture (microM/liter) did not yield a consistent value, nor was the rank order of toxicity the same from these two tests. In hematoxylin and eosin stained slides of major organs from treated mice, no histopathologic lesions were observed which were attributable to administration of these compounds.