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

Eur J Pharm Sci. 2004 Jun;22(2-3):153-64. doi: 10.1016/j.ejps.2004.03.003.

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 ClogP (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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anilides / chemistry
  • Anilides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Middle Aged
  • Nipecotic Acids / chemistry
  • Nipecotic Acids / pharmacology*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation / physiology
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*

Substances

  • Anilides
  • Nipecotic Acids
  • Platelet Aggregation Inhibitors
  • nipecotic acid