Factor VIIa inhibitors: chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model.
Highly selective and potent factor VIIa-tissue factor (fVIIa.TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration-response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox) in the baboon model are also presented.
Young
Wendy B
WB
Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. wendy.young@yahoo.com
Mordenti
Joyce
J
Torkelson
Steven
S
Shrader
William D
WD
Kolesnikov
Aleksandr
A
Rai
Roopa
R
Liu
Liang
L
Hu
Huiyong
H
Leahy
Ellen M
EM
Green
Michael J
MJ
Sprengeler
Paul A
PA
Katz
Bradley A
BA
Yu
Christine
C
Janc
James W
JW
Elrod
Kyle C
KC
Marzec
Ulla M
UM
Hanson
Stephen R
SR
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D008958:Models, Molecular; D010215:Papio; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*
D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa