Bioorganic & Medicinal Chemistry 2000-12-01

Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel 2-aryl substituted pyrid.

P Jakobsen, A M Horneman, E Persson

Index: Bioorg. Med. Chem. 8(12) , 2803-2812, (2000)

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Abstract

The synthesis of a series of 2-aryl substituted hetero annulated 1,3-oxazin-4-ones and their evaluation as specific inhibitors of the tissue factor (TF)/factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.64 to > 40 microM on the activation of factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F and NO2 in the 2-aryl substituent. Some of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being similar in specificity to 2-aryl substituted 4H-3,1-benzoxazin-4-ones described as potential drugs for oral antithrombotic treatment without side effects, such as bleeding, which is observed especially with thrombin inhibitors.