672-87-7

White Solid

Demser,MSD,US,1979

A tyrosine hydroxylase inhibitor. An antihypertensive in pheochromocytoma

ChEBI: An L-tyrosine derivative that consists of L-tyrosine bering an additional methyl substituent at position 2. An inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is us d to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma.

50 g of α-methyl-N-dichloroacetyl-p-nitrophenylalanine was dissolved in 500 ml methanol, 300 mg of platinum oxide were added and the mixture reduced at 41 pounds of pressure; within an hour 14.5 pounds were used up (theory 12.4 pounds). After filtration of the catalyst, the red clear filtrate was concentrated in vacuo and the residual syrup flushed several times with ether. The crystalline residue thus obtained, after air drying, weighed 45.3 g (99.5%), MP unsharp at about 104°C to 108°C with decomposition. After two precipitations with ether from an alcoholic solution, the somewhat hygroscopic amine was dried over sulfuric acid for analysis.
10 g of the amine prepared above was dissolved in 5 ml of 50% sulfuric acid at room temperature; the viscous solution was then cooled in ice and a solution of sodium nitrite (2.4 g) in 10 ml water gradually added with agitation. A flocculent precipitate formed. After all the nitrite had been added, the mixture was aged in ice for an hour, after which it was allowed to warm up to room temperature. Nitrogen came off and the precipitate changed to a sticky oil. After heating on the steam bath until evolution of nitrogen ceased, the oil was extracted with ethyl acetate. After removal of the solvent in vacuo, 9.4 g of colored solid residue was obtained, which was refluxed with 150 ml hydrochloric acid (1:1) for 17 hours. The resulting dark solution; after Norite treatment and extraction with ethyl acetate, was concentrated in vacuo to dryness and the tan colored residue (7.4 g) sweetened with ethanol. Dissolution of the residue in minimum amount of ethanol and neutralization with diethylamine of the clarified solution, precipitated the α-methyl tyrosine, which was filtered, washed with ethanol (until free of chlorides) and ether. The crude amino acid melted at 309°C with decomposition. For further purification, it was dissolved in 250 ml of a saturated sulfur dioxide-water solution, and the solution, after Noriting, concentrated to about 80 ml, the tan colored solid filtered washed with ethanol and ether. Obtained 1.5 g of α-methyl tyrosine, MP 320°C dec.

Demser (Merck).

Tyrosine hydroxylase inhibitor

Metyrosine (α-Methyl-L-tyrosine, Demser). Althoughinhibition of any of the three enzymes involved in CA biosynthesisshould decrease CAs, inhibitors of the first andthe rate-limiting enzyme TH would be the most effective.As such, metyrosine is a much more effective competitiveinhibitor of E and NE production than agents that inhibitany of the other enzymes involved in CA biosynthesis. Itis often possible to “fool” the enzymes into accepting astructurally similar and unnatural substrate such as metyrosine.Metyrosine differs structurally from tyrosine onlyin the presence of an α-methyl group . It is oneexample of a CA-biosynthesis inhibitor in clinical use.Although metyrosine is used as a racemic mixture, it is the (-)isomer that possesses the inhibitory activity.Metyrosine, which is given orally in dosages ranging from 1 to 4 g/day, is used principally for the preoperative managementof pheochromocytoma, chromaffin cell tumorsthat produce large amounts of NE and E. Although theseadrenal medullary tumors are often benign, patients frequentlysuffer hypertensive episodes. Metyrosine reducesthe frequency and severity of these episodes by significantlylowering CA production (35%–80%). The drug ispolar (log P＝0.73) and excreted mainly unchanged in theurine. Because of its limited solubility in water caused byintramolecular bonding of the zwitterions, crystalluria is apotential serious side effect. It can be minimized by maintaininga daily urine volume of more than 2 L. Inhibitors ofCA synthesis have limited clinical utility because suchagents nonspecifically inhibit the formation of all CAs andresult in many side effects. Sedation is the most commonside effect of this drug.
A similar example is the use of α-methyl-m-tyrosine inthe treatment of shock. It differs structurally from metyrosineonly in the presence of m-OH instead of p-OH inmetyrosine. This unnatural amino acid is accepted by the enzymesof the biosynthetic pathway and converted tometaraminol (an α-agonist).

α-Methyl-L-tyrosine (L-AMPT) acts as a competitive inhibitor of tyrosine hydroxylase and inhibits the conversion of tyrosine to L-DOPA and eventually lowers dopamine synthesis in cytosol. AMPT at low concentrations can be used as a potent therapeutic for refractory dystonia or dyskinesia. It also helps in decreasing catecholamine concentration in pheochromocytoma patients.

Metyrosine, (?)|á-methyltyrosine (12.3.11), is synthesized in a few different ways, the simplest of which is the synthesis from 4-methoxybenzylacetone, which is reacted with potassium cyanide in the presence of ammonium carbonate to give the hydantoin (12.3.9). Treating this with hydrogen iodide removes the methyl-protecting group on the phenyl hydroxyl group and the product (12.3.10) is hydrolyzed by barium hydroxide into a racemic mixture of |á-methyl-D,L-tyrosine, from which the desired L-isomer is isolated (12.3.11) [83¨C86].

Store at -20°C