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© 1990 Oxford University Press

other

Some Novel Inhibitors of Platelet Aggregation: Acute Toxicity in Mice and Its Relationship to in vitro Efficacy and Toxicity

II. Nipecotoylaminoalkane and Nipecotoylpiperazine Congeners

W. H. LAWRENCE, A. LASSLO1, J. E. TURNER*, Z. FENG and S. E. BOND

Department of Medicinal Chemistry, College of Pharmacy, The Health Science Center, University of Tennessee Memphis, Tennessee 38163 *Department of Biologic and Diagnostic Sciences, College of Dentistry, The Health Science Center, University of Tennessee Memphis, Tennessee 38163

Received May 9, 1989; accepted August 22, 1989

Some Novel Inhibitors of Platelet Aggregation: Acute Toxicity in Mice and Its Relationship to in vitro Efficacy and Toxicity. II. Nipecotoylaminoalkane and Nipecotoylpiperazine Congeners. LAWRENCE, W. H., LASSLO, A., TURNER, J. E., FENG, Z., AND BOND, S. E. (1990). Fundam. Appl. Toxicol. 14, 356–363. 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 µmol/kg) [Tm] to concentration inhibiting 50% ADP-induced platelet aggregation (µmol/liter) [A] is calculated for each compound. These ratios range from 2.41 to 24.92 for the four compounds included in this study


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