(2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate

Description

ADHD is a neurobehavioral disorder characterized by varying degrees of inattention, hyperactivity, and impulsivity. ADHD is typically diagnosed in childhood and affects 7–12% of the pediatric population in the United States with the condition often enduring into adulthood. While the precise mechanism of action of lisdexamfetamine in treating ADHD is not known, amphetamines are believed to inhibit the reuptake of the neurotransmitters dopamine and noradrenaline (norepinephrine), thereby increasing their presynaptic availability and release into extraneuronal space. The prodrug is constructed by the condensation of D-amphetamine with the activated ester (N-hydroxysuccinimide) of bis-tert-butoxycarbonylprotected L-lysine. Lisdexamfetamine is ultimately generated by treatment with hydrochloric acid in dioxane.
The most common adverse events, comparable to other amphetamine formulations, were decreased appetite, insomnia, upper abdominal pain, and irritability. Lisdexamfetamine is contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate-to-severe hypertension, hyperthyroidism, known hypersensitivity to the sympathomimetic amines, glaucoma, a predisposition to agitated states, and a history of drug abuse. In addition, the drug should not be administered during or within 14 days of treatment with monoamine oxidase inhibitors. It has also been noted that psychostimulants may exacerbate symptoms of pre-existing psychotic disorders, so caution and close observation are recommended in this patient population.

Description

Lisdexamfetamine (mesylate) (Item No. 18050) is an analytical reference material categorized as an amphetamine. Its chemical structure consists of D-amphetamine (Item Nos. 14204 | 15650) coupled with the essential amino acid L-lysine. Lisdexamfetamine is an inactive prodrug that is converted to D-amphetamine upon cleavage of the lysine via enzymatic hydrolysis in red blood cells. Lisdexamfetamine is regulated as a Schedule II compound in the United States. This product is intended for research and forensic applications.

Originator

New River Pharmaceuticals (US)

Uses

Treatment of atten tion deficit hyperactivity disorder (ADHD).

brand name

Vyvanse

Synthesis

The straightforward synthesis of lisdexamfetamine mesilate was initiated by adding a solution of D-amphetamine (66) to a solution of Boc-L-Lys(Boc)-OSu (65), N-methylmorpholine and 1,4-dioxane. The resulting mixture was partitioned between isopropyl acetate and an acetic acid/brine solution, and the organic layer was washed with aqueous sodium bicarbonate to give Boc-L-Lys(Boc)- D-amphetamine (67) in 91% yield. The two primary amine groups were liberated by reacting a solution of 67 in 1,4- dioxane with methanesulfonic acid providing lisdexamfetamine mesilate (X) in 92% yield.

References

[1] J. ERMER G F M Pennick. Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy[J]. Clinical Drug Investigation, 2016, 36 1: 341-356. DOI: 10.1007/s40261-015-0354-y
[2] CHRISTOPHER STEER. Lisdexamfetamine dimesylate: a new therapeutic option for attention-deficit hyperactivity disorder.[J]. CNS drugs, 2012, 26 8: 691-705. DOI: 10.2165/11634340-000000000-00000