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.
Footnotes
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This study was funded entirely by Wyeth Research.
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P.W.B. and V.C. contributed equally to this work.
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The following oral presentations included data in this manuscript for Biacore and the rat carotid model. Data from static cell assay, acute surgical inflammation, and venous thrombosis models have not been presented earlier. Bedard PW, Sushkova N, Eppihimer MJ, Tavares J, Harding K, Darby A, Keith JC Jr, Kaila N, et al. (2006) A novel P-selectin inhibitor, PSI-697, demonstrates positive activity after oral administration in Rodent Models of Vascular Inflammation. 35th Annual New England Pharmacologists Meeting; 2006 Waltham, MA (oral presentation); and Bedard PW, Clerin V, Sushkova N, Darby A, DeBernardo S, Eppihimer MJ, Harding K, Janz K, Kaila N, Keith JC Jr, et al. (2005) A novel P-selectin inhibitor, PSI-697, demonstrates positive activity after oral administration in rodent models of vascular inflammation. International Society of Thrombosis and Haemostasis Meeting; 2005 Sydney, Australia (oral presentation).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.128124.
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ABBREVIATIONS: PSGL, P-selectin glycoprotein ligand; PSI-697, 2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] quinoline-4-carboxylic acid; BSA, bovine serum albumin; HBSS, Hanks' balanced salt solution; PK, pharmacokinetics; ASI, acute surgical inflammation; IVM, intravital microscopy; rPSGL-Ig, recombinant PSGL-1 Ig chimera; KF389789, (E)-3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-1,4-thiaz epin-5-yl]-4-hydroxy-6-methyl-2H-pyran-2-one; OC229-648, 3-(4-{4-[4-((E)-2-carboxy-vinyl)-phenyl]-5-[4-(2-hexadecylcarbamoyl-vinyl)-phenyl]-1H-imidazol-2-yl}-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid; TBC-1269 (bimosiamose), 1,6-bis[3-(3-carboxymethylphenyl)-4-(O-alpha-d-mannopyranosyl)-phenyl] hexane.
- Received July 11, 2007.
- Accepted November 14, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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