Valbenazine | Treatment of Drug-induced Dyskinesia | Treatment of Tardive Dyskinesia | Vesicular Monoamine Transporter 2 (VMT2) Inhibitor

Valbenazine [L-valine (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-yl ester] is a novel, highly selective, vesicular monoamine transporter 2 (VMT2) inhibitor. This agent has a slowed cleavage, low VMAT2 interaction and an attenuated maximum concentration. Chemically, Valbenazine is a prodrug of the purified parent drug of the (+)-a-isomer of Tetrabenazine. Dosing of this inert parent molecule, which must first be transformed to the selective and potent active metabolite, reduces the pharmacokinetic variability. Valbenazine allows an only once-daily administration [1].

Valbenazine: 2D and 3D Structure

Vesicular monoamine transporter 2 function (VMAT2) is responsible for the monoamine transport from cellular cytosol into the synaptic vesicles. Compounds, like tetrabenazine, dihydrotetrabenazine, amphetamine and methamphetamine, bind at distinct VMAT2 sites of this membrane protein and inhibit its activity. As a result, monoamine concentrations reduce in the synaptic cleft and therefore, tardive syndromes improve [1, 2].

Valbenazine received a granted breakthrough drug status in October 2014 by the US-FDA. Valbenazine is being tested in clinical trials for the treatment of patients with tardive dyskinesia.

Tardive Syndromes: Causes and Cures

Tardive syndromes (TS) are a group of delayed-onset abnormal involuntary movement disorders induced by a dopamine receptor blocking agent. There are several phenomenologically distinct types of TS. In this form of dyskinesia, the involuntary movements are tardive, meaning they have a slow or belated onset [2]. They are:

a. Tardive dyskinesia has been used to refer to the TS that presents with rapid, repetitive, stereotypic movements mostly involving the oral, buccal, and lingual areas.

b. Tardive dystonia can be focal, segmental, or generalized. It commonly affects the face and neck followed by the arms and trunk. It usually results in retrocollis when it involves the neck and trunk arching backwards when it involves the trunk.

c. Tardive akathisia is characterized by a feeling of inner restlessness and jitteriness with an inability to sit or stand still.

Other tardive syndromes include tardive tics, myoclonus, tremor, and withdrawal-emergent syndrome.

This term was first used in the early 1960s. At that time, tardive syndromes were more and more observed due to the increasing use of so-called typical neuroleptics, such as phenothiazine-derived drugs or butyrophenones. Up to 30% of patients, exposed to typical neuroleptics, suffer from a tardive syndrome sooner or later. Due to the increased incidence of tardive syndromes, the so-called atypical antipsychotic drugs were developed and introduced in the 1970s. Atypical neuroleptics, such as the dibenzazepines clozapine, olanzapine or quetiapine, show a reduced risk for onset of a tardive syndrome.

The etiology of tardive syndromes is not known.

Atypical neuroleptics such as clonazepam; amantadine; levetiracetam; piracetam and bioactive molecules such as propranolol; vitamin B6; ginkgo biloba; reserpine; anticholinergics and, in particular, tetrabenazine, may provide some symptomatic relief from tardive syndromes. In case of tetrabenazine, enantiomers derived from a-tetrabenazine are active VMAT2 inhibitors. They contribute to the therapeutic effects of the drug. The two dihydrotetrabenazine derivatives of b-tetrabenazine are antagonists at the dopamine D2 receptor. They may particularly induce sedation and parkinsonism, both of which is often observed during chronic racemic-tetrabenazine intake [1].

VMAT2 Inhibitors for Improving Tardive Syndromes

Vesicular monoamine transporter 2 function (VMAT2) is responsible for the monoamine transport from cellular cytosol into the synaptic vesicles. Compounds, like tetrabenazine, dihydrotetrabenazine (including Valbenazine), amphetamine and methamphetamine, bind at distinct VMAT2 sites of this membrane protein and inhibit its activity. As a result, monoamine concentrations reduce in the synaptic cleft and therefore, tardive syndromes improve.

Dosages and Approvals:

Valbenazine (Tradename: Ingrezza) is discovered and developed by Neurocrine Biosciences pharmaceuticals. Valbenazine allows an only once-daily administration. It is still not approved.

Reported Activities for Valbenazine:

Valbenazine causes reversible reduction of dopamine release at the nerve terminal by selectively inhibiting the pre-synaptic human vesicular monoamine transporter type 2 (VMAT2).  In vitro, Valbenazine is a highly selective inhibitor of human VMAT2 showing little or no affinity for VMAT1, other receptors (eg, dopamine D2 receptors), transporters, and ion channels [3].

Active Metabolite of Valbenazine

The activities are reported for Valbenazine and its active metabolite:

K_i (VMAT2 affinity from competition binding studies) = 187, 1.9 nM

%Inhibition (Dopamine D2S (h) receptor @ 10 uM) = 2, -6

%Inhibition (Dopamine D4.4 (h) receptor @ 10 uM) = 13, 0

Summary

Common name: NBI-98854; NBI 98854; NBI98854; Valbenazine

Trademarks: Ingrezza

Molecular Formula: C24H38N2O4

CAS Registry Number: -

CAS Name: (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-ol((2R,3R,11bR)-dihydrotetrabenazine)

Molecular Weight: 418.58

SMILES: CC(C)C[C@H]1[C@H]OC([C@H]C(C)C)N)=O)C[C@@]2([H])N(CCC3=C2C=C(OC)C(OC)=C3)C1

InChI Key: GEJDGVNQKABXKG-CFKGEZKQSA-N

InChI: InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1

Mechanism of Action: Vesicular Monoamine Transporter 2 Inhibitors; VMT2 Inhibitors

Activity: Treatment of Drug-induced Dyskinesia; Treatment of Tardive Dyskinesia; Neuropsychotherapeutics

Status: Phase III (US)

Chemical Class: Tetrabenazine; Dihydrotetrabenazine; Amides; Amino Acids; Small-molecules; L-valine

Originator: Mitsubishi Tanabe Pharma Corporation/Neurocrine Biosciences

Valbenazine Synthesis

WO2008058261A1: The patent reports the process that can easily be carried on a big industrial set-up. It also reports VMAT2 and dopamine receptor activities for various analogues synthesized.

The preparation starts with dimethylamine hydrochloride, 5-methyl-2-hexanone and paraformaldehyde to give 3-Dimethylaminomethyl-5 -methyl-hexan-2-one, which was then converted into methiodide. It was later heated at 80 0C overnight with 6,7-dimethoxy-3,4-dihydroisoquinoline to give racemic Tetrabenazine (TBZ). Four enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35 ⁰C. The next step was carried with (3R,11bR)-Tetrabenazine, which was dissolved in EtOH and cooled to 0 ⁰C. Sodium borohydride was then added in portions at 0 ⁰C. The reaction was complete after 30 minutes and quenched with saturated NH₄Cl, providing the corresponding alcohol. The crude product was purified via flash column chromatography, and the next step was carried with molecule with (2R,3R,11bR) configuration. The desired (2R,3R,11bR) enantiomer was dissolved in anhydrous DCM. Subsequently DMAP and CBz-L-valine was added. Later DCC was added, where a white precipate of the desired product was obtained.

Eur J Med Chem 2011, 46(5), 1841-1848: The article reports resolution of Tetrabenazine (TBZ) using camphor sulphonic acid (CSA). Stereoselective synthesis of all eight dihydrotetrabenazines (DHTBZ) stereoisomers is also reported. Activity against VMAT2 reveals that all dextrorotatory enantiomers exhibited dramatically more potent VMAT2 binding affinity than their corresponding levorotatory isomers.

Identifications:

1H NMR Estimated for Valbenazine

Sideeffects: Valbenazine or placebo was given once per day starting at 25 mg and then escalated by 25 mg to a maximum of 75 mg based on dyskinesia and tolerability assessment. The most common adverse events(AEs) (active vs. placebo) were fatigue and headache (9.8% vs. 4.1%) and constipation and urinary tract infection (3.9% vs. 6.1%). No clinically relevant changes in safety assessments were noted.

Others: From the pharmacological point of view, Valbenazine may be more specific and efficacious against tardive dyskinesia in comparison with tetrabenazine. Valbenazine requires once a day application and thus eases compliance. More frequent intakes are necessary during treatment with tetrabenazine. Patients with underlying schizophrenia, depression or schizoaffective disorders tend to have adherence problems. Therefore, future valbenazine use will be advantageous in comparison with tetrabenazine. Generally, the weakness of VMAT2 inhibition is that it only provides some symptomatic relief but no cure from tardive dyskinesia. VMAT2 inhibition results in diminished monoamine neurotransmitter levels in the synaptic cleft. Therefore, the likelihood increases for the development of a syndrome characterized by parkinsonism with balance problems and depression-related symptoms, such as irritability, anxiety, somnolence, sedation and fatigue.

Though the developers are very exicted about Valbenazine and plan to extend its study in treatment of other disorders including Tourette syndrome, etc.

References:

1. Muller, T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs 2015, 24(6), 737-742. (FMO only)

2. Fernandez, H. H.; et. al. Classification and treatment of tardive syndromes. Neurologist 2003, 9(1), 16-27. (FMO only)

3. Gano, K. W. Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol compounds and methods relating thereto. WO2008058261A1

4. Yao, Z.; et. al. Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors. Eur J Med Chem 2011, 46(5), 1841-1848. (FMO only) [ Good work. Nice Read !!!!]

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