Investigation of platelet aggregation inhibitory activity by phenyl amides and esters of piperidinecarboxylic acids

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• 作者：de Candia ; Modesto ; Summo ; Luciana ; Carrieri ; Antonio ; Altomare ; Cosimo ; Nardecchia ; Adele ; et. al.
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2003
• 出版时间：April, 2003
• 年：2003
• 卷：11
• 期：7
• 页码：1439-1450
• 全文大小：285 K

文摘

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 IC₅₀ value being close to that of the most active bis-3-carbamoylpiperidines reported in literature (ca. 40 μM) and aspirin (ca. 60 μM) 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 (r²