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    CAS 1025504-45-3

    PharmaCompass
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    2D Structure
    Also known as: 1025504-45-3, Ingrezza, Mt-5199, Nbi 98854, 54k37p50kh, (2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2h- benzo(a)quinolizin-2-yl l-valinate
    Molecular Formula
    C24H38N2O4
    Molecular Weight
    418.6  g/mol
    InChI Key
    GEJDGVNQKABXKG-CFKGEZKQSA-N
    FDA UNII
    54K37P50KH
    Valbenazine (development name NBI-98854) has been used in trials studying the treatment and basic science of Tourette Syndrome and Tardive Dyskinesia. In April, 2017, valbenazine was approved by the FDA (as Ingrezza) as the first and only approved treatment for adults with Tardive Dyskinesia (TD).
    Valbenazine is a Vesicular Monoamine Transporter 2 Inhibitor. The mechanism of action of valbenazine is as a Vesicular Monoamine Transporter 2 Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate
    2.1.2 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
    2.1.3 InChI Key
    GEJDGVNQKABXKG-CFKGEZKQSA-N
    2.1.4 Canonical SMILES
    CC(C)CC1CN2CCC3=CC(=C(C=C3C2CC1OC(=O)C(C(C)C)N)OC)OC
    2.1.5 Isomeric SMILES
    CC(C)C[C@@H]1CN2CCC3=CC(=C(C=C3[C@H]2C[C@H]1OC(=O)[C@H](C(C)C)N)OC)OC
    2.2 Other Identifiers
    2.2.1 UNII
    54K37P50KH
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. (2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2h- Benzo(a)quinolizin-2-yl L-valinate

    2. Ingrezza

    3. Nbi-98854

    4. Valine 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2h-benzo(a)quinolizin-2-yl Ester

    2.3.2 Depositor-Supplied Synonyms

    1. 1025504-45-3

    2. Ingrezza

    3. Mt-5199

    4. Nbi 98854

    5. 54k37p50kh

    6. (2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2h- Benzo(a)quinolizin-2-yl L-valinate

    7. 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

    8. 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

    9. Valbenazine [usan]

    10. Valbenazine [usan:inn]

    11. Unii-54k37p50kh

    12. Valbenazine [mi]

    13. Valbenazinenbi-98854

    14. Valbenazine [inn]

    15. Valbenazine (usan/inn)

    16. Valbenazine [who-dd]

    17. Gtpl8694

    18. Chembl2364639

    19. Schembl15932979

    20. Dtxsid801026306

    21. Ex-a2002

    22. Bdbm50573733

    23. Mfcd28963976

    24. Zinc43195697

    25. Cs-5908

    26. Db11915

    27. Ncgc00522306-02

    28. [(2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1h-benzo[a]quinolizin-2-yl] (2s)-2-amino-3-methylbutanoate

    29. Ac-30929

    30. As-35294

    31. Hy-16771

    32. Valine 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2h-benzo(a)quinolizin-2-yl Ester

    33. D10675

    34. Nbi-98854;nbi98854;nbi 98854

    35. Q27089118

    36. (2r,3r,11br)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-yl L-valinate

    37. (s)-2-amino-3-methyl-butyric Acid (2r,3r,11br)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a]isoquinolin-2-yl Ester

    38. [(2r,3r,11br)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1h-pyrido[2,1-a]isoquinolin-2-yl] (2s)-2-amino-3-methylbutanoate

    2.4 Create Date
    2008-05-26
    3 Chemical and Physical Properties
    Molecular Weight 418.6 g/mol
    Molecular Formula C24H38N2O4
    XLogP34.3
    Hydrogen Bond Donor Count1
    Hydrogen Bond Acceptor Count6
    Rotatable Bond Count8
    Exact Mass418.28315770 g/mol
    Monoisotopic Mass418.28315770 g/mol
    Topological Polar Surface Area74 Ų
    Heavy Atom Count30
    Formal Charge0
    Complexity569
    Isotope Atom Count0
    Defined Atom Stereocenter Count4
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    For the treatment of tardive dyskinesia in adults.

    FDA Label

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    Valbenazine decreases the availability of monoamine neurotransmitters by preventing their storage in synaptic vesicles. This is believed to be the reason behind its therapeutic effect in tardive dyskinesia although the exact mechanism is unknown.

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    VALBENAZINE
    5.2.2 FDA UNII
    54K37P50KH
    5.2.3 Pharmacological Classes
    Vesicular Monoamine Transporter 2 Inhibitors [MoA]; Vesicular Monoamine Transporter 2 Inhibitor [EPC]
    5.3 ATC Code

    N - Nervous system

    N07 - Other nervous system drugs

    N07X - Other nervous system drugs

    N07XX - Other nervous system drugs

    N07XX13 - Valbenazine

    5.4 Absorption, Distribution and Excretion

    Absorption

    Oral bioavailability of 49%. Tmax of 0.5-1h.

    Route of Elimination

    Roughly 60% is excreted in urine and 30% in feces. Less than 2% if the parent compound or active metabolite was excreted unchanged.

    Volume of Distribution

    92 Liters.

    Clearance

    7.2 Liters/hour.

    5.5 Metabolism/Metabolites

    Valbenzine is extensively metabolized to one active metabolite [+]--dihydrotetrabenazine ([+]--HTBZ) through hydrolysis of the valine ester reaching Cmax within 4-8 hours. It is also metabolized via oxidation by CYP3A4/5 to a mono-oxidzed metabolite NBI-136110 which also appears to pharmacologically active. [+]--HTBZ is metabolized by CYP2D6.

    5.6 Biological Half-Life

    Both valbenazine and its active metabolite [+]--HTBZ have a half life of 15-22 hours.

    5.7 Mechanism of Action

    Valbenazine and its active meabolites bind to and inhibit vesicular monoamine transporter 2 (VMAT2)with high selectivity (valbenazine Ki = 150nM, [+]--HTBZ Ki = 1.98nM, NBI136110 Ki = 160nM) with no significant binding to VMAT1 (Ki <10microM for each). This prevents the reuptake and storage of monoamine neurotransmitters noradrenaline, dopamine, and serotonin in synaptic vesicles making them vulnerable to metabolism by cytosolic enzymes. The presynaptic release of monoamine neurotransmitters is decreased due to the lack of vesicles with packaged neurotransmitter ready for release into the synapse. Neither valbenazine nor its active metabolite exhibit significant off target binding at dopamine, serotonin, or adrenaline receptors or uptake transporters at 10microM concentrations.