Enantioselective antiplatelet actions of nipecotamides

Abstract Two synthetic racemic nipecotamides, 1-decyl-3-(N,N-diethylcarbamoyl)piperidine hydrobromide ( 1 ) and α,α'-bis[3-(N-benzyl-N-methylcarbamoyl)piperidino]- p -xylene dihydrobromide ( 2 ) were resolved on a chiral α 1 -acid glycoprotein semipreparative HPLC column. Thus, rac . 1 was resolved into two enantiomers 1A -(+) and 1B -(-); rac . 2 was separated into the optical antipodes 2A -(-) and 2C -(+), and the meso diastereomer 2B -(0). Also on a preparative scale, 97% pure 2C was obtained via diastereomeric salt formation using dibenzoyl-L-(-)-tartaric acid. The individual isomers were evaluated for their platelet aggregation inhibitory potency. In inhibiting ADP-induced aggregation of human platelets in vitro , 1B -(-) was 4 times more potent than its optical antipode 1A -(+), and 2C -(+) was 6 times as active as 2A -(-); the meso diastereomer 2B -(0) had intermediate activity. With collagen as the agonist, 1B -(-) was twice as active as 1A -(+), and 2C -(+), the most active compound in this series (IC 50 = 0.96 μM), was 10 times more potent than its antipode 2A -(-). Again, the meso diastereomer 2B -(0) had intermediate activity. These results demonstrate the enantioselective antiplatelet actions of mono- and bis- nipecotamide derivatives.