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CAS 1025504-45-3

CAS 1025504-45-3

Chemistry

Chemistry

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

CAS 1025504-45-3

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 Formula	C₂₄H₃₈N₂O₄
Molecular Weight	418.6 g/mol
XLogP3	4.3
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	8
Exact Mass	418.28315770 g/mol
Monoisotopic Mass	418.28315770 g/mol
Topological Polar Surface Area	74 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	569
Isotope Atom Count	0
Defined Atom Stereocenter Count	4
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

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.