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  • Through an extensive SAR optimization campaign with the hydr

    2023-01-31

    Through an extensive SAR optimization campaign with the 4-((2-hydroxy-3-methoxybenzyl)amino)-benzenesulfonamide-based scaffold researchers have developed ML355 ((N-benzo[d]thiazol-2-yl)-4((2-hydroxy-3 methoxybenzyl)amino)benzenesulfonamide) [5]. ML355 is a nonreductive, noncompetitive, reversible 12-LOX inhibitor with high selectivity (>50-fold) over other oxygenases. Similar to other 12-LOX inhibitors, in vitro ML355 reduces human platelet aggregation in response to low doses of agonists, but the antiplatelet effects of blocking 12-LOX can be overcome at higher concentrations of agonist 5, 32. ML355 has also been shown to inhibit platelet activation mediated by the immune receptor, FcγRIIa [32]. Since FcγRIIa signaling in platelets is required for immune-mediated thrombocytopenia such as heparin-induced thrombocytopenia (HIT), our laboratory is currently testing ML355 in mouse models of HIT. Importantly, pharmacokinetic studies with ML355 in mice determined that it is orally bioavailable and has no observable toxic effects. Oral gavage of mice with ML355 twice daily for 2 days potently decreased thrombus formation in an injury-induced cremaster arteriole thrombosis model and impaired vessel occlusion in an FeCl3-induced thrombosis model. Surprisingly, ML355 treatment of mice only minimally affected hemostasis in laser-induced rupture of the cremaster muscle arterial or saphenous vein [57]. In ex vivo flow chamber assays with human whole blood, ML355 attenuated platelet adhesion and aggregation on collagen-coated surfaces under arterial shear forces more potently than aspirin did [57]. These data suggest that ML355 is the best lead rac1 inhibitor and represents a viable approach for first-in-class and potentially a first-in-human approach for a novel target to decrease platelet reactivity following vascular insult or injury, while minimizing the increased risk of bleeding that is concomitant with antiplatelet therapy. It will be important moving forward to delineate any unforeseen off-target effects and potential toxicity prior to human studies. However, it is reasonable to predict that this orally bioavailable inhibitor of the platelet 12-LOX will soon be tested in phase I safety tests in humans and represents a new approach to limiting platelet activation and thrombosis in man.
    Concluding Remarks Antiplatelet therapies have decreased the incidence and mortality of ischemic heart disease and stroke; however, the potency of antiplatelet agents is limited by the subsequent increase in risk of severe bleeding inherent to current antiplatelet therapies. The goal for the development of novel antiplatelet therapy is to identify a target that is required for pathological intravascular thrombus formation, but dispensable for normal hemostasis. While several candidates have emerged as potential antiplatelet targets it remains controversial whether thrombosis can be selectively targeted without affecting hemostasis. Accumulating data suggest that 12-LOX represents a viable novel antiplatelet target. 12-LOX has been shown to be an important regulator of platelet activation and thrombus formation whose expression is predominantly restricted to the platelets and its progenitor cells, the megakaryocytes. Excitingly, the orally bioavailable 12-LOX inhibitor, ML355, limits thrombosis formation without significant prolongation of hemostasis in murine models [57]. Furthermore, ML355 decreases human platelet accumulation on collagen in ex vivo whole blood perfusion chamber assays. A secondary area of regulation in the vessel where 12-LOX is known to play an important role is in inflammation. 12-LOX has been shown to help promote inflammation in murine models of rheumatoid arthritis, suggesting that 12-LOX also plays an essential role in regulation of chronic inflammatory diseases [58]. Inhibiting 12-LOX may be one mechanism by which acute and chronic inflammation is attenuated. While recent published work by several research groups supports 12-LOX as a viable antiplatelet therapy, further work is required to establish 12-LOX as a clinical target in people at risk for a thrombotic event associated with only a limited risk for bleeding (see Outstanding Questions). Continued understanding of the underlying mechanisms by which 12-LOX and its oxylipins elicit their effects in platelets, blood, and blood vessels will be essential for translating this promising new thrombotic target from benchside discovery to treatment in humans.