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
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
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 |
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
Cmax
Value | Dose | Co-administered | 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 | Co-administered | 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 |
T1/2
Value | Dose | Co-administered | 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: |
unhealthy, CHILD n = 20 Health Status: unhealthy Condition: spasms syndrom Age Group: CHILD Sex: M+F Food Status: UNKNOWN Population Size: 20 Sources: |
Disc. AE: Leukopenia... AEs leading to discontinuation/dose reduction: Leukopenia (mild, 1 pt) Sources: |
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: |
unhealthy n = 98 Health Status: unhealthy Condition: seizures Sex: M+F Food Status: UNKNOWN Population Size: 98 Sources: |
Disc. AE: rash... AEs leading to discontinuation/dose reduction: rash (4.1%) Sources: |
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: |
unhealthy, CHILD n = 20 Health Status: unhealthy Condition: spasms syndrom Age Group: CHILD Sex: M+F Food Status: UNKNOWN Population Size: 20 Sources: |
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: |
unhealthy n = 98 Health Status: unhealthy Condition: seizures Sex: M+F Food Status: UNKNOWN Population Size: 98 Sources: |
PubMed
Title | Date | PubMed |
---|---|---|
Future prospects for the drug treatment of epilepsy. | 2001 |
|
The new generation of GABA enhancers. Potential in the treatment of epilepsy. | 2001 |
|
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 |
|
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 |
|
Newer GABAergic agents for pharmacotherapy of infantile spasms. | 2002 Oct |
|
The contraceptive agent Provera enhances GABA(A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids? | 2003 Nov 5 |
|
Role of neurosteroids in catamenial epilepsy. | 2004 Dec |
|
Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice. | 2004 Jul |
|
[Perspectives of neurosteroid derivative application in antiepileptic therapy]. | 2005 |
|
Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats. | 2006 Apr |
|
Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy. | 2006 Jun |
|
Diverse mechanisms of antiepileptic drugs in the development pipeline. | 2006 Jun |
|
[A new aspect in the research on antiepileptic drugs]. | 2007 Feb |
|
Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). | 2007 Jan |
|
Treatment of Lennox-Gastaut syndrome: overview and recent findings. | 2008 Dec |
|
Modifications of antiepileptic drugs for improved tolerability and efficacy. | 2008 Feb 14 |
|
Role of brain inflammation in epileptogenesis. | 2008 Feb 29 |
|
Neurosteroid replacement therapy for catamenial epilepsy. | 2009 Apr |
|
Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. | 2009 Mar-Apr |
|
"Epileptic encephalopathy" of infancy and childhood: electro-clinical pictures and recent understandings. | 2010 Dec |
|
Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats. | 2010 Dec |
|
Anticonvulsant doses of ganaxolone do not compromise motor performance in immature rats. | 2010 Jan 29 |
|
Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. | 2010 May |
|
Emerging drugs for partial onset seizures. | 2010 Sep |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01963208
200 mg and 225 mg capsules; target dose 1800 mg/day dosed 900mg 2x/day
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/9067315
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
Edited
Fri Dec 15 16:35:38 GMT 2023
by
admin
on
Fri Dec 15 16:35:38 GMT 2023
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Record UNII |
98WI44OHIQ
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Record Status |
Validated (UNII)
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Record Version |
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
578017
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FDA ORPHAN DRUG |
473515
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NCI_THESAURUS |
C265
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FDA ORPHAN DRUG |
489215
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FDA ORPHAN DRUG |
833521
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DEA NO. |
2401
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FDA ORPHAN DRUG |
547116
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FDA ORPHAN DRUG |
929822
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FDA ORPHAN DRUG |
81894
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GANAXOLONE
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C105051
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