四唑
化学
对抗
药理学
血栓素
受体
血小板
立体化学
生物化学
生物
医学
内科学
作者
Massimo Bertinaria,Mohammed Abrar Abdul Gaffar Shaikh,Carola Buccellati,Clara Cena,Barbara Rolando,Loretta Lazzarato,Roberta Fruttero,Alberto Gasco,Malvina Hoxha,Valérie Capra,Angelo Sala,G. Enrico Rovati
出处
期刊:ChemMedChem
[Wiley]
日期:2012-08-02
卷期号:7 (9): 1647-1660
被引量:29
标识
DOI:10.1002/cmdc.201200272
摘要
Abstract A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX‐2 inhibition and thromboxane A 2 prostanoid (TP) receptor antagonism. The compounds were synthesized through a copper‐catalyzed coupling procedure and characterized for their p K a values. TP receptor antagonism was assessed on human platelets; COX‐2 inhibition was determined on human isolated monocytes and human whole blood. TPα receptor binding of the most promising compounds was evaluated through radioligand binding assays. Some of the isosteric substitutions at the carboxylic acid group afforded compounds with improved TP receptor antagonism; of these, a tetrazole derivative retained good COX‐2 inhibitory activity and selectivity. The identification of this tetrazole acting as a balanced dual‐acting compound in human whole blood, along with SAR analysis of the synthesized lumiracoxib derivatives, might contribute to the rational design of a new class of cardioprotective anti‐inflammatory agents.
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