Fluorinated dual antithrombotic compounds based on 1,4-benzoxazine scaffold

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).

Antithrombotic compounds possessing both thrombin inhibitory and GPIIb/IIIa receptor antagonistic activity.Figure optionsDownload 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.