Design and synthesis of piperidine-3-carboxamides as human platelet aggregation inhibitors.
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 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 approximately 7 A. It is suggested that van der Waals forces and pi interactions may govern the inhibitor-platelet interaction. The most potent type 6 inhibitor was alpha,alpha'-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 A from each other and connected by a hydrophobic well.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163.
X
X
Zheng
S R
SR
Salgia
W B
WB
Thompson
E O
EO
Dillingham
S E
SE
Bond
Z
Z
Feng
K R
KR
Prasad
R
R
Gollamudi
D000328:Adult; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005260:Female; D006801:Humans; D008297:Male; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D009557:Nipecotic Acids; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors