Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans

Abstract

BackgroundPlatelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P‐selectin antagonist PSI‐697 on platelet–monocyte aggregate formation in humans.Methods and ResultsIn a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral PSI‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI‐697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (P>0.05). P‐selectin‐blocking antibody (CLB‐Thromb6), but not PSI‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (P<0.001).ConclusionsThe novel small‐molecule P‐selectin antagonist PSI‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established.Clinical Trial RegistrationURL: http://EudraCT.ema.europa.eu Unique identifier: 2007‐005695‐14.

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

“…Examples include an orally administered, C2 benzyl substituted, quinolone salicylic acid [131]. PSI-697 was the first of two drugs in this class and in clinical trials did not show beneficial inhibition on platelet-monocyte aggregation [132]. Further modification of this compound has yielded PSI-421, which demonstrated improved pharmacokinetics and has been found to be effective in animal models of both arterial and venous injury [131].…”

“…Specifically, the pan-selectin inhibitor GMI-1070 has been noted to have low activity against P-selectin with an IC 50 of 423 µM [119], and bimosiamose (TBC1269) has similarly been noted to have an IC 50 of 70 µM [133]. Likewise, even selective P-selectin inhibitors such as PSI-697 and PSI-421 have weak binding affinity with Kd’s of approximately 200 µM[131, 134]. …”

Platelet adhesion on endothelium early after vein grafting mediates leukocyte recruitment and intimal hyperplasia in a murine model

“…In clinical practice, P-selectin inhibitors are promising drug candidates. (130,131). For instance, the pan-selectin antagonist GMI-1070 reverses microemboli formation in acute vascular occlusion in a mouse model of sickle cell disease and successfully increases blood flow and decreases biomarkers of endothelial activation and leukocyte activation in patients with sickle cell anemia in a phase 1 clinical trial (132,133).…”

Systemic and Flap Inflammatory Response Associates with Thrombosis in Flap Venous Crisis

“…P-selectin is a marker for platelet activation that participates in the early stage of thrombosis. Elevated levels of P-selectin have been identified in a number of conditions including cigarette smoking, diabetes mellitus, hypertension, and acute coronary syndrome [11,12]. The primary function of vWF is facilitation of platelet attachment to sites of blood vessel injury.…”