title: Factor VIIa inhibitors: gaining selectivity within the trypsin family.
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.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. bill.shrader@celera.com
authors.forename: William D
authors.initials: WD
authors.lastname: Shrader
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: Jana
authors.initials: J
authors.lastname: Burgess-Henry
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
authors.forename: John
authors.initials: J
authors.lastname: Hendrix
authors.forename: Huiyong
authors.initials: H
authors.lastname: Hu
authors.forename: Steve
authors.initials: S
authors.lastname: Torkelson
authors.forename: Tony
authors.initials: T
authors.lastname: Ton
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Katz
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Ronnel
authors.initials: R
authors.lastname: Cabuslay
authors.forename: Ellen
authors.initials: E
authors.lastname: Sanford
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sprengeler
mesh_terms: D001665:Binding Sites; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D011485:Protein Binding; D011516:Prothrombin / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism
chemical_list: D065427:Factor Xa Inhibitors; D011516:Prothrombin; D015942:Factor VIIa; D014357:Trypsin