Author/Authors :
William D. Shrader، نويسنده , , Aleksandr Kolesnikov، نويسنده , , Jana Burgess-Henry، نويسنده , , Roopa Rai، نويسنده , , John Hendrix Hinshaw، نويسنده , , Huiyong Hu، نويسنده , , Steve Torkelson، نويسنده , , Tony Ton، نويسنده , , Wendy B. Young، نويسنده , , Mary E. McGrath and Bradley A. Katz، نويسنده , , Christine Yu، نويسنده , , Jie Tang، نويسنده , , Ronnel Cabuslay، نويسنده , , Ellen Sanford، نويسنده , , James W. Janc، نويسنده , , Paul A. Sprengeler، نويسنده ,
Abstract :
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.
Keywords :
factor Xa , fIIa , Selectivity , Amidine , thrombin , crystallography , inhibitor , Factor VIIa , Trypsin , Lysine-192 , Suzuki
