GANAXOLONE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H36O2
Molecular Weight	332.52
Optical Activity	UNSPECIFIED
Defined Stereocenters	8 / 8
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@@]3([H])[C@@]2([H])CC[C@@]4([H])C[C@](C)(O)CC[C@]34C

InChI

InChIKey=PGTVWKLGGCQMBR-FLBATMFCSA-N

InChI=1S/C22H36O2/c1-14(23)17-7-8-18-16-6-5-15-13-20(2,24)11-12-21(15,3)19(16)9-10-22(17,18)4/h15-19,24H,5-13H2,1-4H3/t15-,16-,17+,18-,19-,20+,21-,22+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C22H36O2
Molecular Weight	332.52
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	8 / 8
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17199022 | http://www.marinuspharma.com/ganaxolone/

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) (GNX) is the 3beta-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. GNX is an allosteric modulator of GABA(A) receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. GNX has been shown to be well tolerated in adults and children. In early phase II studies, GNX has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures. Ganaxolone is a CNS-selective GABAA modulator being developed in three different dose forms (IV, capsule, and liquid) intended to maximize therapeutic reach to adult and pediatric patients in both acute and chronic care settings.Ganaxolone is a synthetic analog of endogenous allopregnanolone, which has been shown to be an effective anticonvulsant by restoring electrical balance to the seizing brain. While allopregnanolone’s anticonvulsant and anti-anxiety activities are well documented, allopregnanolone has the potential to convert back to its metabolic precursor progesterone, which could lead to hormonal side effects. Ganaxolone has been designed with an added methyl group that prevents back conversion to an active steroid which unlocks ganaxolone’s potential for chronic use. In preclinical studies, ganaxolone exhibited potency and efficacy comparable to allopregnanolone. Both ganaxolone and allopregnanolone bind to GABAA at the synaptic and extrasynaptic binding sites. Activity with extrasynaptic GABAA receptors are of particular importance for treating patients who developed tolerance to benzodiazepines and barbiturates. Ganaxolone binds to the GABAA receptors, which opens the pore to allow chloride ions to move into the postsynaptic neuron, leading to the inhibition of neurotransmission.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GABA-A receptor; agonist GABA site 13 Target ID: CHEMBL2109244 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9067315 \| https://www.ncbi.nlm.nih.gov/pubmed/25799373	Positive Allosteric Modulator 179		103.0 nM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Partial epilepsies 1 Sources: http://adisinsight.springer.com/drugs/800004287 http://www.marinuspharma.com/ganaxolone/	Primary	Phase III 656	Unknown Approved Use Unknown
Epilepsy 121 Sources: http://adisinsight.springer.com/drugs/800004287 http://www.marinuspharma.com/ganaxolone/	Primary	Phase II 1132	Unknown Approved Use Unknown
Fragile X syndrome 7 Sources: http://adisinsight.springer.com/drugs/800004287 http://www.marinuspharma.com/ganaxolone/	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
106.23 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
32.34 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	50 mg 1 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
376.03 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
130 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11232855	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
1093.13 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
235.53 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	50 mg 1 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
3103.04 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
668 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11232855	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
65.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
37.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9579942	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
6.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/11232855	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	GANAXOLONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
36 mg/kg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 36 mg/kg, 1 times / day Route: oral Route: multiple Dose: 36 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11074186	unhealthy, CHILD n = 20 Health Status: unhealthy Condition: spasms syndrom Age Group: CHILD Sex: M+F Food Status: UNKNOWN Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/11074186	Disc. AE: Leukopenia... AEs leading to discontinuation/dose reduction: Leukopenia (mild, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/11074186
1500 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 1500 mg, 1 times / day Route: oral Route: multiple Dose: 1500 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28230252	unhealthy n = 98 Health Status: unhealthy Condition: seizures Sex: M+F Food Status: UNKNOWN Population Size: 98 Sources: https://pubmed.ncbi.nlm.nih.gov/28230252	Disc. AE: rash... AEs leading to discontinuation/dose reduction: rash (4.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/28230252

AEs

AE	Significance	Dose	Population
Leukopenia	mild, 1 pt Disc. AE	36 mg/kg 1 times / day multiple, oral (total daily dose) Highest studied dose Dose: 36 mg/kg, 1 times / day Route: oral Route: multiple Dose: 36 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11074186	unhealthy, CHILD n = 20 Health Status: unhealthy Condition: spasms syndrom Age Group: CHILD Sex: M+F Food Status: UNKNOWN Population Size: 20 Sources: https://pubmed.ncbi.nlm.nih.gov/11074186
rash	4.1% Disc. AE	1500 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 1500 mg, 1 times / day Route: oral Route: multiple Dose: 1500 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28230252	unhealthy n = 98 Health Status: unhealthy Condition: seizures Sex: M+F Food Status: UNKNOWN Population Size: 98 Sources: https://pubmed.ncbi.nlm.nih.gov/28230252

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P0036JU	https://www.1pchem.com/search?query=1P0036JU
Alfa Chemistry	ACM38398322	http://www.alfa-chemistry.com/search.aspx?q=ACM38398322
Angene	AGN-PC-00B4JN	http://www.angenechemical.com/productshow/AGN-PC-00B4JN.html
ApexBio Technology	B7092	https://www.apexbt.com/catalogsearch/result/?q=B7092
AstaTech	42708	http://astatechinc.com/CPSResult.php?CRNO=42708
BLD Pharm	BD131879	http://www.bldpharm.com/search/Search.html?keyword=BD131879
BOC Sciences	38398-32-2	http://www.bocsci.com/description.asp?cas=38398-32-2
Cayman Chemical	20919	http://www.caymanchem.com/app/template/Product.vm/catalog/20919
Combi-Blocks	QJ-2869	http://www.combi-blocks.com/cgi-bin/find.cgi?QJ-2869
Fluorochem	468419	http://www.fluorochem.co.uk/Products/Product?code=468419
KeyOrganics	AS-35253	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-35253
Lab Network	LN01306507	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01306507
MolPort	MolPort-023-276-471	https://www.molport.com/shop/molecule-link/MolPort-023-276-471
MolPort	MolPort-039-331-718	https://www.molport.com/shop/molecule-link/MolPort-039-331-718
MuseChem	R019134	https://www.musechem.com/product/R019134.html
Tetrahedron	TS78025	http://www.thsci.com/search.do?q=TS78025
Tocris	2531	https://www.tocris.com/search.php?Type=QuickSearch&Value=2531
eMolecules	36500412	https://orderbb.emolecules.com/search/#?query=36500412
eMolecules	44487931	https://orderbb.emolecules.com/search/#?query=44487931
eMolecules	50419189	https://orderbb.emolecules.com/search/#?query=50419189
mcule	MCULE-1576448380	https://mcule.com/MCULE-1576448380/

PubMed

Title	Date	PubMed
Anticonvulsant and behavioral effects of neuroactive steroids alone and in conjunction with diazepam.	1997 Aug	9262314
The new generation of GABA enhancers. Potential in the treatment of epilepsy.	2001	11475940
A high-performance liquid chromatography-tandem mass spectrometric method for the determination of pharmacokinetics of ganaxolone in rat, monkey, dog and human plasma.	2001 Feb 10	11232855
Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons.	2001 Sep 23	11557091
Changes in GABA(A) receptor gene expression induced by withdrawal of, but not by long-term exposure to, ganaxolone in cultured rat cerebellar granule cells.	2002 Dec	12438522
Newer GABAergic agents for pharmacotherapy of infantile spasms.	2002 Oct	12582452
Catamenial epilepsy: pathophysiology, diagnosis, and management.	2003 Sep 1	14504304
Role of neurosteroids in catamenial epilepsy.	2004 Dec	15579299
[Perspectives of neurosteroid derivative application in antiepileptic therapy].	2005	16512623
Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats.	2006 Apr	16174428
Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.	2006 Jun	16631210
Diverse mechanisms of antiepileptic drugs in the development pipeline.	2006 Jun	16621450
[A new aspect in the research on antiepileptic drugs].	2007 Feb	17299237
Ganaxolone.	2007 Jan	17199022
Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII).	2007 Jan	17158031
Treatment of Lennox-Gastaut syndrome: overview and recent findings.	2008 Dec	19337447
Modifications of antiepileptic drugs for improved tolerability and efficacy.	2008 Feb 14	19787095
Role of brain inflammation in epileptogenesis.	2008 Feb 29	18306464
Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease.	2008 Mar	17629950
Current trends in the treatment of infantile spasms.	2009	19557123
Neurosteroid replacement therapy for catamenial epilepsy.	2009 Apr	19332335
Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX).	2009 Jan	19008076
Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions.	2009 Mar-Apr	19443931
Neurosteroids: endogenous role in the human brain and therapeutic potentials.	2010	21094889
Anticonvulsant action of a new analogue of allopregnanolone in immature rats.	2010	19537924
"Epileptic encephalopathy" of infancy and childhood: electro-clinical pictures and recent understandings.	2010 Dec	21629447
Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X).	2010 Dec	20970964
Anticonvulsant doses of ganaxolone do not compromise motor performance in immature rats.	2010 Jan 29	20026384
Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model.	2010 May	20172694
Emerging drugs for partial onset seizures.	2010 Sep	20476851

Patents

Sample Use Guides

In Vivo Use Guide

200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day

Route of Administration: Oral

In Vitro Use Guide

Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:35:38 GMT 2023` Edited by `admin` on `Fri Dec 15 16:35:38 GMT 2023`
Record UNII	98WI44OHIQ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

GANAXOLONE

Official Name

English

GANAXOLONE [MI]

Common Name

English

3.ALPHA.-HYDROXY-3-METHYL-5.ALPHA.-PREGNAN-20-ONE

Systematic Name

English

ZTALMY

Brand Name

English

GANAXOLONE [USAN]

Common Name

English

CCD1042

Code

English

DEA NO. 2401

Code

English

PREGNAN-20-ONE, 3-HYDROXY-3-METHYL-, (3.ALPHA.,5.ALPHA.)-

Common Name

English

ganaxolone [INN]

Common Name

English

3α-hydroxy-3β-methyl-5α-pregnan-20-one

Systematic Name

English

CCD-1042

Code

English

Ganaxolone [WHO-DD]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

578017