Antiplatelet activity of nipecotamides in experimental thrombosis in mice

A group of nipecotamides (3-carbamoylpiperidines) were designed, synthesized, and evaluated for their ability to protect platelets from induced aggregation. An in vivo mouse thrombosis model was used to determine the protection afforded by these compounds from sudden thrombotic death induced by intravenous collagen plus epinephrine. Enantioselectivity appears to play a pivotal role in determining the activity of these 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, alpha,alpha'-bis[3-(N-benzyl-N-methylcarbamoyl)-piperidino]-p-xyle ne dihydrobromide (4) was the most potent in preventing induced intravascular platelet aggregation in mice, with a 50% effective dose of (ED50) of 27.5 mumol (20 mg)/kg.