Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides

Abstract

Using N -[4-(hexyloxy)phenyl]piperidine-3-carboxamide ( 17c ) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5′-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure–activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC 50 and lipophilicity, as assessed by RP-HPLC capacity factors and Clog P (i.e. calculated 1-octanol–water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of β-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n -propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.