Investigation of platelet aggregation inhibitory activity by phenyl amides and esters of piperidinecarboxylic acids.
A series of anilides and phenyl esters of piperidine-3-carboxylic acid (nipecotic acid) were synthesized and tested for the ability to inhibit aggregation of human platelet rich-plasma triggered by adenosine 5'-diphosphate (ADP) and adrenaline. As a rule, amides were about two times more active than the corresponding esters, and derivatives bearing substituents at the para position of the phenyl ring were significantly more active than the meta-substituted ones. Among the tested compounds, 4-hexyloxyanilide of nipecotic acid (18a) was found to be the most active one, its IC(50) value being close to that of the most active bis-3-carbamoylpiperidines reported in literature (ca. 40 micro M) and aspirin (ca. 60 microM) in ADP- and adrenaline-induced aggregation, respectively. Compared with the isomeric 4-hexyloxyanilides of piperidine-2-carboxylic (pipecolinic) and piperidine-4-carboxylic (isonipecotic) acids, compound 18a showed higher activity, and a Hansch-type quantitative structure-activity relationship (QSAR) study highlighted lipophilicity and increase in electron density of the phenyl ring as the properties which mainly increase the antiplatelet activity (r(2)=0.74, q(2)=0.64). The interaction of nipecotoyl anilides with phosphatidylinositol, a major component of the inner layer of the platelet membranes, was investigated by means of flexible docking calculation methods to give an account of a key event underlying their biological action.
de Candia
Modesto
M
Dipartimento Farmaco-chimico, Università degli Studi, Via Orabona 4, 70125, Bari, Italy.
Summo
Luciana
L
Carrieri
Antonio
A
Altomare
Cosimo
C
Nardecchia
Adele
A
Cellamare
Saverio
S
Carotti
Angelo
A
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000577:Amides / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology; D002021:Buffers; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004952:Esters / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009557:Nipecotic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D000577:Amides; D002021:Buffers; D002264:Carboxylic Acids; D004952:Esters; D007202:Indicators and Reagents; D009557:Nipecotic Acids; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D004837:Epinephrine