title: 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 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.
authors.affiliation: Dipartimento Farmaco-chimico, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: De Marco
authors.forename: Modesto
authors.initials: M
authors.lastname: De Candia
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Erica
authors.initials: E
authors.lastname: De Candia
authors.forename: Cosimo
authors.initials: C
authors.lastname: Altomare
mesh_terms: D000328:Adult; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008875:Middle Aged; D009557:Nipecotic Acids / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000813:Anilides; D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; C030278:nipecotic acid