Enantioselective antiplatelet actions of nipecotamides.
Two synthetic racemic nipecotamides, 1-decyl-3-(N,N- diethylcarbamoyl)piperidine hydrobromide (1) and alpha, alpha'-bis[3-(N-benzyl-N-methylcarbamoyl)piperidino]-p-xylene dihydrobromide (2) were resolved on a chiral alpha 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 1B-(-) was twice as active as 1A-(+), and 2C-(+), the most active compound in this series (IC50 = 0.96 microM), 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.
Gollamudi
R
R
Department of Medicinal Chemistry, College of Pharmacy, University of Tennessee-Memphis 38163.
Feng
Z
Z
Dillingham
E O
EO
Bond
S E
SE
Han
G
G
Salgia
S
S
D000244:Adenosine Diphosphate / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009557:Nipecotic Acids / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; C077875:alpha,alpha'-bis(3-(N-benzyl-N-methylcarbamoyl)piperidinol)-4-xylene; C077874:1-decyl-3-(N,N-diethylcarbamoyl)piperidine; D000244:Adenosine Diphosphate; D003094:Collagen