Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity

Abstract

Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington’s disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson’s disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.

Real-Time Monitoring of Solid–Liquid Slurries: Optimized Synthesis of Tetrabenazine

“…TBZ is an active pharmaceutical ingredient prescribed for the management of neuromuscular symptoms arising from Huntington’s disease . The TBZ derivative valbenazine (VBZ, 2 ; Figure ) received FDA approval in 2017 and is marketed as Ingrezza (Neurocrine Biosciences Inc., San Diego, CA) to treat tardive dyskinesia, a similar neuromuscular disorder. , VBZ is a particularly potent compound because it is metabolized in vivo to the single, highly bioactive stereoisomer (+)-α-dihydrotetrabenazine ((2 R ,3 R ,11b R )-HTBZ), while the metabolic pathway of TBZ is not stereoselective. , These factors have incited interest in optimizing the synthesis of TBZ as a route to VBZ.…”

Donafenib treatment for hepatocellular carcinoma

“…According to the published literature, there are >10 ways to synthesize deuterium-containing drugs, which means that they can be produced on a kilogram scale. [ 12 , 13 ] Many pharmaceutical producers have started switching toward the deuterated form of drugs. A new era of deuterated drugs has begun.…”

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery

“…For example, commercially available d 3 -methyl sources (e.g., CD 3 I, CD 3 OD, and CD 3 NH 2 • HCl) are frequently utilized for the syntheses of target compounds, including the approved heavy drugs deutetrabenazine and deucravacitinib (Figure 1B). [11,12,[15][16][17]31,32] Additionally, the 5-(d 3 -methyl)dibenzothiophenium salt derived from CD 3 OD and dibenzothiophene was recently developed as a chemoselective and electrophilic d 3 -methylating reagent. [33] To diversify heavy drugs, various d n -alkylated reagents, such as d 3 -methyl, d 2 -ethyl, d 2 -phenethyl, and other d 2 -alkyl-substituted compounds, have been prepared, and their pharmaco-kinetics evaluated (Figure 1C).…”