Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors

Article abstract of DOI:10.1021/jm00001a023

A detailed structure-activity analysis was carried out using eight 1- alkyl(aralkyl)nipecotamides (type 5), 33 bis-nipecotamidoalkanes and aralkanes (type 6), and 7 N,N'-bis(nipecotoyl)-piperazines (type 7) as inhibitors of human platelet aggregation. Steric factors played an important role in determining the activity of type 5 compounds possessing an appropriate degree of hydrophobic character. Types 6 and 7 compounds were more potent than the corresponding type 5 molecules. Hydrophobic character appeared to influence the activity of type 6 compounds. A 3-substituent on the piperidine ring was necessary for antiplatelet activity; the substituent should be preferably an amide with its C attached directly to the ring. 3,5- Disubstitution and 2-substitution led to a decline in activity. Optimal activity was attained when the two nipecotoyl ring N atoms were connected by an aralkyl group, and separated by ~7 ?. It is suggested that van der Waals forces and π interactions may govern the inhibitor-platelet interaction. The most potent type 6 inhibitor was α,α'-bis[3-(N-ethyl-N- butylcarbamoyl)piperidino]-p-xylene (6i). The most potent type 5 compound was 1-decyl-3-(N,N-diethylcarbamoyl)piperidine (5a). Any substitution on the piperazine ring of type 7 compounds led to a decline in activity, the most active analog being N,N'-bis(1-decylnipecotoyl)piperazine (7a). It is suggested that nipecotamides interact with anionic platelet sites located 7 ? from each other and connected by a hydrophobic well.