Towards dual antithrombotic compounds - Balancing thrombin inhibitory and fibrinogen GPIIb/IIIa binding inhibitory activities of 2,3-dihydro-1,4-benzodioxine derivatives through regio- and stereoisomerism

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• 作者：Milo&scaron ; Ili?^a ; Petra Dunkel^b ; Janez Ila&scaron ; ^a ; Ewa Chabielska^c ; Agnieszka Zakrzeska^c ; Pé ; ter Má ; tyus^b ; ; Danijel Kikelj^a ; ^{danijel.kikelj@ffa.uni-lj.si}
• 关键词：Antithrombotic ; Thrombin inhibitor ; GPIIb/IIIa ; 2 ; 3-dihydro-1 ; 4-benzodioxine ; Dual antithrombotic compound ; Multitarget
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：62
• 期：Complete
• 页码：329-340
• 全文大小：835 K

文摘

Enantiomers of 2,3-dihydro-1,4-benzodioxine derivatives possessing both thrombin and fibrinogen GPIIb/IIIa binding inhibitory activities were prepared from (R)- and (S)-glycidol as potential dual antithrombotic compounds. The influence of chirality and substitution pattern on thrombin inhibition and on inhibition of fibrinogen binding to GPIIb/IIIa was analyzed. Docking studies were used in an attempt to rationalize the results. The (S)-isomers of both 2,3-dihydro-1,4-benzodioxine regioisomers at positions 6 and 7 were found to be better thrombin inhibitors than the corresponding (R)-enantiomers, whereas we observed that stereochemistry does not display a consistent influence on fibrinogen GPIIb/IIIa binding inhibitory activity. Compound 11b, the (S)-isomer of the 6-substituted regioisomer, possessed the best balanced dual activity, with K_i(thrombin)?=?1.67?¡À?0.27?¦ÌM and IC_{50(GPIIb/IIIa)}?=?0.665?¡À?0.26?¦ÌM, raising the hope that merging anticoagulant and platelet antiaggregatory activities in the same molecule could lead to successful multitarget antithrombotic agents.