title: Factor VIIa inhibitors: chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model.
abstract: 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.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. wendy.young@yahoo.com
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.forename: Joyce
authors.initials: J
authors.lastname: Mordenti
authors.forename: Steven
authors.initials: S
authors.lastname: Torkelson
authors.forename: William D
authors.initials: WD
authors.lastname: Shrader
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Huiyong
authors.initials: H
authors.lastname: Hu
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Leahy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Green
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sprengeler
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Katz
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Elrod
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Marzec
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
mesh_terms: 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*
chemical_list: D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa