Gollamudi R, Feng Z, Dillingham E O, Bond S E, Han G, Salgia S
Department of Medicinal Chemistry, College of Pharmacy, University of Tennessee-Memphis 38163.
Thromb Res. 1993 Feb 15;69(4):361-7. doi: 10.1016/0049-3848(93)90035-m.
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.
两种合成外消旋烟酰胺哌啶化合物，1-癸基-3-(N,N-二乙基氨基甲酰基)哌啶氢溴酸盐(1)和α,α'-双[3-(N-苄基-N-甲基氨基甲酰基)哌啶基]-对二甲苯二氢溴酸盐(2)在手性α1-酸性糖蛋白半制备HPLC柱上进行拆分。因此，外消旋体1拆分为两种对映体1A-(+)和1B-(-)；外消旋体2分离为旋光对映体2A-(-)和2C-(+)，以及内消旋非对映体2B-(0)。同样在制备规模上，通过使用二苯甲酰-L-(-)-酒石酸形成非对映体盐获得了97%纯的2C。对各个异构体的血小板聚集抑制效力进行了评估。在体外抑制ADP诱导的人血小板聚集方面，1B-(-)的效力是其对映体1A-(+)的4倍，2C-(+)的活性是2A-(-)的6倍；内消旋非对映体2B-(0)具有中等活性。以胶原蛋白为诱导剂时，1B-(-)的活性是1A-(+)的两倍，而该系列中活性最高的化合物2C-(+)(IC50 = 0.96 microM)，其效力是其对映体2A-(-)的10倍。同样，内消旋非对映体2B-(0)具有中等活性。这些结果证明了单-和双-烟酰胺哌啶衍生物的对映体选择性抗血小板作用。
