Article ID Journal Published Year Pages File Type
1394514 European Journal of Medicinal Chemistry 2012 9 Pages PDF
Abstract

Fluorinated 3,4-dihydro-2H-1,4-benzoxazine derivatives possessing both thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activities were prepared as potential dual antithrombotic compounds. Fluorine scan (3-fluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl and 3,5-difluorobenzyl substituted compounds) was performed in order to obtain 6-(carboxymethyl)(3,4-difluorobenzyl)amino compound (9i) as the most potent compound with balanced dual activity (Ki(Thr) = 0.33 ± 0.07 μM, IC50(GP IIb/IIIa) = 1.1 ± 0.6 μM).

Graphical abstractAntithrombotic compounds possessing both thrombin inhibitory and GPIIb/IIIa receptor antagonistic activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Compounds with thrombin inhibitory and GP IIb/IIIa receptor antagonistic activity. ► New fluorinated 3,4-dihydro-2H-1,4-benzoxazines with benzamidine moiety. ► Fluorine scan with 3-fluoro-, 4-fluoro-, 3,4-difluoro-, 3,5-difluorobenzyl moiety. ► Optimized substitution pattern for active and balanced dual antithrombotic compounds. ► The most potent and well balanced lead compound has activity close to the nanomolar range.

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