Inhibitors of the tissue factor/factor VIIa-induced coagulation: Synthesis and in vitro evaluation of novel 2-aryl substituted pyrido[3,4-d][1,3]-, pyrido[2,3-d][1,3]-, pyrazino[2,3-d][1,3]-, pyrimido[4,5-d][1,3]-, pyrazolo[3,4-d][1,3]-, thieno[3,2-d][1,3]- and thieno[2,3-d][1,3]-oxazin-4-ones

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 >40μM 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. Copyright (C) 2000 Elsevier Science Ltd.