Factor VIIa inhibitors: gaining selectivity within the trypsin family.
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.
Shrader
William D
WD
Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. bill.shrader@celera.com
Kolesnikov
Aleksandr
A
Burgess-Henry
Jana
J
Rai
Roopa
R
Hendrix
John
J
Hu
Huiyong
H
Torkelson
Steve
S
Ton
Tony
T
Young
Wendy B
WB
Katz
Bradley A
BA
Yu
Christine
C
Tang
Jie
J
Cabuslay
Ronnel
R
Sanford
Ellen
E
Janc
James W
JW
Sprengeler
Paul A
PA
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
D065427:Factor Xa Inhibitors; D011516:Prothrombin; D015942:Factor VIIa; D014357:Trypsin