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.
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 microM. 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.
Bedard
Patricia W
PW
Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. pbedard@wyeth.com
Clerin
Valerie
V
Sushkova
Natalia
N
Tchernychev
Boris
B
Antrilli
Thomas
T
Resmini
Christine
C
Keith
James C
JC
Hennan
James K
JK
Kaila
Neelu
N
Debernardo
Silvano
S
Janz
Kristin
K
Wang
Qin
Q
Crandall
David L
DL
Schaub
Robert G
RG
Shaw
Gray D
GD
Carter
Laura L
LL
D000818:Animals; D004195:Disease Models, Animal; D018922:HL-60 Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D019007:P-Selectin / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014657:Vasculitis / Q000188:drug therapy* / Q000378:metabolism; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000378:metabolism
D006912:Hydroxyquinolines; D019007:P-Selectin; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid