MK-571 sodium salt hydrate (Synonyms: L-660711)

MK-571 sodium salt hydrate, as a potent and specific antagonist of leukotriene D4 action, used for treatment of asthma^[1].

In vitro test it shown that with 0.01-100 µM MK-571 reduced the export of 3H-S1P from erythrocytes in a concentration-dependent manner^[2]. In vitro efficacy test it exhibited that 12.5-50 µM MK-571 in both aortic and brain derived ECs has more obvious supress-the efflux of agents rate than that of verapamil^[3]. MK-571 has inhibition against LTC4 transport with IC50 of 1.0 µM^[4].

In vivo, treatment with 8-32 mg/kg MK-571 intravenously in mice caused dose-dependent protection against acetic-acid-induced abdominal constriction with ED50 of 30 mg/kg^[5]. In vivo, mice were instilled after endotoxin instillation at doses of 15, 35, or 50 mg/kg, MK-571 obviously inhibited the influx of inflammatory cells and reduced pro-inflammatory cytokines in BALF in a dose-dependent manner^[6]. In addition, 10 ug/eye completely inhibited in vivo chemotactic responses to LTD4, and partially inhibited (54%) the responses to ovalbumin^[7]. In vivo, pretreatment with 1 mg/kg MK-571 orally markedly inhibited the OA(ovalbumin)-induced EO (eosinophils) migration^[8] . Treatment with 1 mg/kg/day MK-571 for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, MK-571 had effective inhibition of myointimal VSMC (vascular smooth muscle cell) proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening^[9].

References:

[1] Tocco DJ, et al. Interspecies differences in stereoselective protein binding and clearance of MK-571. Drug Metab Dispos. 1990 Jul-Aug;18(4):388-92.

[2] Christensen PM, et al. Apolipoprotein M mediates sphingosine-1-phosphate efflux from erythrocytes. Sci Rep. 2017 Nov 8;7(1):14983.

[3] Eilers M, et al. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood). 2008 Sep;233(9):1149-60.

[4] Schaub T, et al. ATP-dependent leukotriene export from mastocytoma cells. FEBS Lett. 1991 Feb 11;279(1):83-6.

[5] Gök S, et al. The antinociceptive effect of leukotriene D(4) receptor antagonist, MK-571, in mice: possible involvement of opioidergic mechanism. Eur J Pharmacol. 1999 Dec 15;386(2-3):195-200.

[6] Hao Q, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Decrease Lung Injury in Mice. J Immunol. 2019 Oct 1;203(7):1961-1972.

[7] Chan CC, et al. Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. Eur J Pharmacol. 1990 Dec 4;191(3):273-80.

[8] Foster A, et al. Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Int Arch Allergy Appl Immunol. 1991;96(3):279-84.

[9] Porreca E, et al. Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Thromb Haemost. 1996 Jul;76(1):99-104.