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Characterization of the Novel P-Selectin Inhibitor PSI-697 [2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] Quinoline-4-carboxylic acid] in Vitro and in Rodent Models of Vascular Inflammation and Thrombosis

Authors :
Bedard, Patricia W.
Clerin, Valerie
Sushkova, Natalia
Tchernychev, Boris
Antrilli, Thomas
Resmini, Christine
Keith, James C.
Hennan, James K.
Kaila, Neelu
DeBernardo, Silvano
Janz, Kristin
Wang, Qin
Crandall, David L.
Schaub, Robert G.
Shaw, Gray D.
Carter, Laura L.
Source :
The Journal of Pharmacology and Experimental Therapeutics; February 2008, Vol. 324 Issue: 2 p497-506, 10p
Publication Year :
2008

Abstract

P-selectin plays a significant and well documented role in vascular disease by mediating leukocyte and platelet rolling and adhesion. This study characterizes the in vitro activity, pharmacokinetic properties, and the anti-inflammatory and antithrombotic efficacy of the orally active P-selectin small-molecule antagonist PSI-697 [2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] quinoline-4-carboxylic acid; molecular mass, 367.83]. Biacore and cell-based assays were used to demonstrate the ability of PSI-697 to dose dependently inhibit the binding of human P-selectin to human P-selectin glycoprotein ligand-1, inhibiting 50% of binding at 50 to 125 μM. The pharmacokinetics of PSI-697 in rats were characterized by low clearance, short half-life, low volume of distribution, and moderate apparent oral bioavailability. A surgical inflammation model, using exteriorized rat cremaster venules, demonstrated that PSI-697 (50 mg/kg p.o.) significantly reduced the number of rolling leukocytes by 39% (P< 0.05) versus vehicle control. In a rat venous thrombosis model, PSI-697 (100 mg/kg p.o.) reduced thrombus weight by 18% (P< 0.05) relative to vehicle, without prolonging bleeding time. Finally, in a rat carotid injury model, PSI-697 (30 or 15 mg/kg p.o.) administered 1 h before arterial injury and once daily thereafter for 13 days resulted in dose-dependent decreases in intima/media ratios of 40.2% (P= 0.025) and 25.7% (P= 0.002) compared with vehicle controls. These data demonstrate the activity of PSI-697 in vitro and after oral administration in animal models of both arterial and venous injury and support the clinical evaluation of this novel antagonist of P-selectin in atherothrombotic and venous thrombotic indications.

Details

Language :
English
ISSN :
00223565 and 15210103
Volume :
324
Issue :
2
Database :
Supplemental Index
Journal :
The Journal of Pharmacology and Experimental Therapeutics
Publication Type :
Periodical
Accession number :
ejs68441745
Full Text :
https://doi.org/10.1124/jpet.107.128124