ML355 is a selective 12-lipoxygenase inhibitor with an IC50 value of 0.34 µM, with much less potency against 15-LO-1, 15-LO-2, and 5-LO (IC50s = 9.7, >100, and >100 µM).
Human lipoxygenases (LOXs) are enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites as the end product. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation and cell proliferation. ML355 is a potent and selective inhibitor of human 12-lipoxygenase with nM potency. ML355 has been shown to decrease calcium mobilization and PAR-4 induced platelet aggregation in patient derived human platelets and to significantly inhibit AA/IONO-induced (Arachidonic acid and calcium ionophore) 12-HETE (a downstream target of the 12-LOX protein) in mouse BTC3 cells and human islets at 10 µM. Moreover, ML355 demonstrated excellent microsomal stability with both rat (T1/2 >30 minutes) and mouse (T1/2 >300 minutes) and was found to be stable to mouse plasma over a 2 hour period (100% remaining). In vivo PK studies where ML355 was administered as a solution via IV (3 mpk) and PO (30 mpk) demonstrated that ML355 is orally bioavailable (%F = 20) with good half-life (T1/2 = 2.9 hours)[1].
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