ANTIPLATELET ACTIVITY OF NIPECOTAMIDES IN EXPERIMENTAL THROMBOSIS IN MICE

A group of nipecotamides (3-carbamoylpiperidines) were designed, synth esized, and evaluated for their ability to protect platelets from indu ced aggregation. An in vivo mouse thrombosis model was used to determi ne the protection afforded by these compounds from sudden thrombotic d eath induced by intravenous collagen plus epinephrine. Enantioselectiv ity appears to play a pivotal role in determining the activity of thes e compounds. Lipophilicity, whereas previously found to correlate well with in vitro activity, did not directly influence in vivo activity. The presence of an amide function on the 3-position of the piperidine ring was essential for activity. Of the 10 compounds reported here alp ha alpha'-bis[3-(N-benzyl-N-methylcarbamoyl)- piperidino]-p-xylene dih ydrobromide (4) was the most potent in preventing induced intravascula r platelet aggregation in mice, with a 50% effective dose of (ED(50)) of 27.5 mu mol (20 mg)/kg.