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Meldonium (also known as Mildronate, THP, MET-88, Mildronāts or Quaterine) is a clinically used anti-ischemic drug that is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia.] It is used in Lithuania and the Russian Federation,but is not approved by the Food and Drug Administration for use in the United States.
Mechanism of action
The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate, a structural analogue of γ-butyrobetaine, with a NH group replacing the CH2 at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.
The mechanism of action of meldonium is to act as a fatty acid oxidation inhibitor, presumably by inhibiting enzymes in the carnitine biosynthesis pathway such as γ-butyrobetaine hydroxylase. γ-Butyrobetaine hydroxylase is an enzyme that belongs to the 2-oxoglutarate (2OG) oxygenase superfamily and catalyses the formation of L-carnitine from γ-butyrobetaine.X-ray crystallographic and in vitro biochemical studies suggest meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as a competitive substrate/inhibitor to form malonic acid semialdehyde, dimethylamine, formaldehyde, 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid, likely via a Steven's type rearrangementmechanism. Mildronate is a potent γ-butyrobetaine hydroxylase inhibitor, with a half maximal inhibitory concentration (IC50) value of 62 μM. Meldonium is an example of a non-peptidyl substrate mimic inhibitor for human 2OG oxygenase.