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

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 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.

The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors

“…This is of likely clinical importance as these factors represent measures of the final common pathway of platelet aggregation (GPIIb-IIIa) [12]; adhesion of activated platelets to monocytes and neutrophils (P-selectin) [19]; and adhesion of activated platelets to subendothelial collagen in the blood vessel wall (GPIb) [20]. Indeed, FDA-approved drugs (abciximab, integrilin and tirofiban) that block GPIIb-IIIa are of benefit as antithrombotic therapy in acute coronary syndromes [21], and in animal models, antagonism of platelet surface P-selectin [22] and platelet surface GPIb [23] has antithrombotic benefit. The later circadian peaks in aggregability (representing platelet reactivity), platelet count and ATP release suggest that these may not be as relevant to the day/night pattern of increased risk for thromboembolistic events in the morning as the measures of platelet size and platelet surface activated antigens (GPIIb-IIIa, P-selectin, surface GPIb), which represent in vivo circulating activated platelets.…”

“…FDA-approved drugs (abciximab, eptifibatide and tirofiban) that block GPIIb-IIIa (the platelet receptor that we specifically measured by flow cytometry and the receptor upon which whole blood aggregometry is specifically dependent [35]) are of benefit as antithrombotic therapy in acute coronary syndromes [21]. In animal models, antagonism of platelet surface P-selectin [22] and platelet surface GPIb [23] has antithrombotic benefit. A better understanding of the relative importance of circadian rhythms and behaviors on platelet function may help reveal new therapeutic targets for cardiac patients.…”

Selectin inhibitors: a patent review

“…Published data have shown that PSI-697 inhibits P-selectin-dependent leukocyte rolling in mouse and rat [43,44]. It has also shown efficacy in disease models of atherosclerosis in mouse [45], restenosis in rat [43], and venous thrombosis in rat [46] and baboon [47]. A recent publication also shows ex vivo activity in humans inhibiting thrombus formation [48].…”

“…Their lead compound, PSI-697 ( Figure 5), has reached Phase I clinical trials. Published data have shown that PSI-697 inhibits P-selectin-dependent leukocyte rolling in mouse and rat [43,44]. It has also shown efficacy in disease models of atherosclerosis in mouse [45], restenosis in rat [43], and venous thrombosis in rat [46] and baboon [47].…”

A Thought Experiment in Contemporary Drug Development: Informed Bench‐to‐Bedside Strategies

“…The capability of PSI‐697 to inhibit the binding of human P‐selectin to PSGL‐1, reduce leukocyte rolling, modestly reduce venous thrombosis and thrombus weight, and reduce intimal thickness following arterial injury was demonstrated in vivo and in rodent models of vascular inflammation and thrombosis. 14 It also reduced ex vivo thrombus formation in a dose‐dependent manner in humans employing the Badimon Flow Chamber. 15 …”