Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel 2-aryl substituted pyrid.
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.
Jakobsen
P
P
Medicinal Chemistry Research, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark. paj@novo.dk
Horneman
A M
AM
Persson
E
E
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005170:Factor X / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D010078:Oxazines; D005170:Factor X; D013925:Thromboplastin; D015942:Factor VIIa