Author/Authors :
Kazuyuki Sagi، نويسنده , , Koichi Fujita، نويسنده , , Masayuki Sugiki، نويسنده , , Mitsuo Takahashi، نويسنده , , Shunji Takehana، نويسنده , , Kazumi Tashiro، نويسنده , , Takashi Kayahara، نويسنده , , Masahiro Yamanashi، نويسنده , , Yumiko Fukuda، نويسنده , , Seiji Oono، نويسنده , , Akiko Okajima، نويسنده , , Seinosuke Iwata، نويسنده , , Masataka Shoji، نويسنده , , Kuniya Sakurai، نويسنده ,
Abstract :
An inhibitor of the complex of factor VIIa and tissue factor (fVIIa/TF), 2-substituted-4-amidinophenylpyruvic acid 1a, was structurally modified with the aim of increasing its potency and selectivity. The lead compound 1a was originally found in our factor Xa (fXa) inhibitor library on the basis of structural similarity of the primary binding sites of fVIIa and fXa. The design was based on computational docking studies using the extracted active site of fVIIa. Compound 1j was found to inhibit factor VIIa/TF at nanomolar concentration with improved selectivity versus fXa and thrombin and it preferentially prolonged the clotting time in the TF-dependent extrinsic pathway.
