VALNOCTAMIDE

Details

Stereochemistry	MIXED
Molecular Formula	C8H17NO
Molecular Weight	143.2267
Optical Activity	UNSPECIFIED
Defined Stereocenters	0 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC(C)C(CC)C(N)=O

InChI

InChIKey=QRCJOCOSPZMDJY-UHFFFAOYSA-N

InChI=1S/C8H17NO/c1-4-6(3)7(5-2)8(9)10/h6-7H,4-5H2,1-3H3,(H2,9,10)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28605109
Curator's Comment: The description was created based on several sources, including https://www.drugbank.ca/drugs/DB13099 | https://www.ncbi.nlm.nih.gov/pubmed/12948028 | https://www.ncbi.nlm.nih.gov/pubmed/20636634 | https://www.ncbi.nlm.nih.gov/pubmed/24001086

Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities and developed by Beersheva Mental Health Center for treatment mania. Valnoctamide has been marketed as an anxiolytic and sedative in several European countries (as Nirvanil), including Italy, Holland, and Switzerland, until the year 2000 but was not actively promoted as an anticonvulsant. It was marketed in the U.S. as Axiquel by McNeil Laboratories in the 1970s. In mice, valnoctamide has been shown to be distinctly less teratogenic than valproic acid. Injection of 3 mkmol ⁄ kg at day 8 of gestation produced only 1% exencephaly (as compared to 0–1% in control mice and 53% in valproate-treated mice). Embryolethality rates showed similar results: 52% with valproate versus 5% in the controls and 2% with valnoctamide. Valnoctamide's patent is expired, and it is not the property of any major pharmaceutical company. Valnoctamide has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain and is currently being developed for the treatment of mania and Schizoaffective Disorder. In clinical trials, Valnoctamide was well tolerated but lacked efficacy in the treatment of symptoms in patients with acute mania.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GABA-A receptor; anion channel 203 Target ID: CHEMBL2093872 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24995528	Negative Allosteric Modulator 43

Conditions

Condition	Modality	Highest Phase	Product
Mania 3 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20636634	Primary	Phase III 665	Unknown Approved Use Unknown
Cytomegalovirus infection 6 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28630251	Primary	Preclinical	Unknown Approved Use Unknown
Schizoaffective disorder 3 Sources: https://clinicaltrials.gov/ct2/show/NCT00140179	Primary	Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
5.8 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2111246/	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:		VALNOCTAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
71 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2111246/	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:		VALNOCTAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
9.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2111246/	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:		VALNOCTAMIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
500 mg 3 times / day multiple, oral Highest studied dose Dose: 500 mg, 3 times / day Route: oral Route: multiple Dose: 500 mg, 3 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28605109/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/28605109/	Sources: https://pubmed.ncbi.nlm.nih.gov/28605109/

PubMed

Title	Date	PubMed
Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X).	2010-12	20970964
Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial.	2010-06	20636634
Evaluation of the antiallodynic, teratogenic and pharmacokinetic profile of stereoisomers of valnoctamide, an amide derivative of a chiral isomer of valproic acid.	2010-06	20230843
Modifications of antiepileptic drugs for improved tolerability and efficacy.	2008-02-14	19787095
Effect of valproate derivatives on human brain myo-inositol-1-phosphate (MIP) synthase activity and amphetamine-induced rearing.	2007-01-23	17901568
Diverse mechanisms of antiepileptic drugs in the development pipeline.	2006-06	16621450
Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain.	2005-09	15997234
Identification of early-responsive genes correlated to valproic acid-induced neural tube defects in mice.	2005-04	15799026
Polycomb homologs are involved in teratogenicity of valproic acid in mice.	2004-11	15523661
Amidic modification of valproic acid reduces skeletal teratogenicity in mice.	2004-02	14991910
Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy.	2003-08	12948028
In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy.	2000-11	11205735

Patents

Sample Use Guides

In Vivo Use Guide

600 mg ⁄ day (200 mg three times daily) and increased to 1200 mg (400 mg three times daily) after four days. Each patient received valnoctamideor for ﬁve weeks

Route of Administration: Oral

In Vitro Use Guide

Whole-cell recordings of mIPSCs were obtained by voltage clamping the cell at −70 mV (with series resistance compensation) while blocking excitatory currents with 3 mM kynurenic acid (Sigma-Aldrich, St. Louis, MO, USA) and Na+ channel-dependent release with 1 μM TTX (Abcam, Cambridge, UK). Following a 4-min baseline, perfusion solution was switched to an identical solution containing 1 mM valnoctamide (VCD). Drug was applied for 10 min and then washed out in normal recording solution for another 10 min. Flumazenil (FMZ) competition and diazepam (DZP) occlusion experiments were conducted similarly, with the first perfusion change to 500 μM VCD followed by 500 μM VCD + 10 μM FMZ or 1 μM DZP followed by 1 μM DZP + 1 mM VCD, respectively. FMZ and DZP were purchased from Tocris Bioscience (Bristol, UK) and VCD was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). These drugs were dissolved in DMSO at stock concentrations of 1 M (VCD), 10 mM (FMZ and DZP). The final concentration of DMSO then ranged from 0.05–0.2% and was kept constant throughout each experiment.

Name

Type

Language

AXIQUEL

Preferred Name

English

VALNOCTAMIDE

Official Name

English

2-ETHYL-3-METHYL-PENTANAMIDE

Systematic Name

English

valnoctamide [INN]

Common Name

English

Valnoctamide [WHO-DD]

Common Name

English

VALNOCTAMIDE [USAN]

Common Name

English

MCN-X-181

Code

English

VALNOCTAMIDE [MI]

Common Name

English

NSC-34092

Code

English

NSC-32363

Code

English

VALNOCTAMIDE [MART.]

Common Name

English

Classification Tree Code System Code

WHO-ATC

N05CM13