Synthesis and NK 1/NK 2 binding activities of a series of diacyl-substituted 2-arylpiperazines

Abstract

The synthesis and binding affinity for hNK 1 and hNK 2 receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK 1 activity was shown by one enantiomer ( 13a) and NK 2 activity was shown by the other enantiomer ( 13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK 2 active piperazine ( 15) showed that the 2 R configuration was associated with NK 2 activity. Further derivatization indicated that dual NK 1/NK 2 activity could be built into the 2 R series.