Ganaxolone

Identification

Name
Ganaxolone
Accession Number
DB05087
Type
Small Molecule
Groups
Investigational
Description

Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. Ganaxolone is an allosteric modulator of GABAA 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. Ganaxolone has been shown to be well tolerated in adults and children. In early phase II studies, Ganaxolone 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.

Structure
Thumb
Synonyms
Not Available
External IDs
CCD-1042
Categories
UNII
98WI44OHIQ
CAS number
38398-32-2
Weight
Average: 332.528
Monoisotopic: 332.271530399
Chemical Formula
C22H36O2
InChI Key
PGTVWKLGGCQMBR-FLBATMFCSA-N
InChI
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
IUPAC Name
1-[(1S,2S,5R,7S,10R,11S,14S,15S)-5-hydroxy-2,5,15-trimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadecan-14-yl]ethan-1-one
SMILES
[H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC[C@@]2([H])C[C@](C)(O)CC[C@]12C

Pharmacology

Indication

Investigated for use/treatment in pediatric indications and seizure disorders.

Pharmacodynamics

Ganaxolone is a powerful positive allosteric modulator of GABAA receptors with potency and efficacy comparable to its endogenous analog 3a,5a-P (Carter et al., 1997). As with 3a,5a-P, Ganaxolone potentiation of the GABAA receptor occurs at a site distinct from the benzodiazepine site. Ganaxolone has protective activity in diverse rodent seizure models, including clonic seizures induced by pentylenetetrazol (PTZ) and bicuculline (BIC), limbic seizures in the 6 Hz model, and amygdala kindled seizures (Carter et al., 1997; Rogawski and Reddy, 2004; Kaminski et al., 2004).

Mechanism of action

Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the γ-aminobutyric acid type A (GABAA) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals.

TargetActionsOrganism
UGamma-aminobutyric acid receptor subunit alpha-1Not AvailableHuman
UGamma-aminobutyric acid receptor subunit alpha-2Not AvailableHuman
UGamma-aminobutyric acid receptor subunit alpha-3Not AvailableHuman
UGamma-aminobutyric acid receptor subunit alpha-4Not AvailableHuman
UGamma-aminobutyric acid receptor subunit alpha-5Not AvailableHuman
UGamma-aminobutyric acid receptor subunit alpha-6Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

>99%

Metabolism
Not Available
Route of elimination
Not Available
Half life

1.3-1.9 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Nohria V, Giller E: Ganaxolone. Neurotherapeutics. 2007 Jan;4(1):102-5. [PubMed:17199022]
  2. Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O: Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy. Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18. [PubMed:17634060]
External Links
PubChem Compound
6918305
PubChem Substance
175426940
ChemSpider
5293511
BindingDB
50369240
ChEMBL
CHEMBL1568698
Wikipedia
Ganaxolone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingPreventionEpilepsies1
2CompletedTreatmentCatamenial Epilepsy / Epilepsy, Localization Related1
2CompletedTreatmentCessation, Smoking1
2CompletedTreatmentEpilepsy, Complex Partial1
2CompletedTreatmentEpilepsy, Localization Related1
2CompletedTreatmentFragile X Syndrome (FXS)1
2CompletedTreatmentInfantile Spasms (IS)1
2CompletedTreatmentPost Traumatic Stress Disorder (PTSD)1
2RecruitingTreatmentBehavioral Symptoms / Complications, Pregnancy / Depression / Depressive Disorders / Moods Disorders / Postpartum Blues / Postpartum Depression / Postpartum disorder / PPD / Psychiatric Disorder NOS1
2RecruitingTreatmentBehavioral Symptoms / Complications, Pregnancy / Depression / Depressive Disorders / Moods Disorders / Postpartum / Postpartum Depression / PPD / Psychiatric Disorder NOS / Puerperal Disorders1
2RecruitingTreatmentConvulsive Status EPILEPTICUS / Epilepsies / Non Convulsive Status Epilepticus / Refractory seizure disorders1
2TerminatedTreatmentInfantile Spasms (IS)1
3CompletedTreatmentDrug Resistant Partial Onset Seizure1
3RecruitingTreatmentCDKL5 Deficiency Disorder1
3TerminatedTreatmentDrug Resistant Partial Onset Seizure1
Not AvailableCompletedTreatmentMajor Depressive Disorder (MDD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000712 mg/mLALOGPS
logP4.37ALOGPS
logP4.27ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)19.1ChemAxon
pKa (Strongest Basic)-1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity97.54 m3·mol-1ChemAxon
Polarizability40.68 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.984
Caco-2 permeable+0.8629
P-glycoprotein substrateSubstrate0.5627
P-glycoprotein inhibitor IInhibitor0.5153
P-glycoprotein inhibitor IINon-inhibitor0.6722
Renal organic cation transporterNon-inhibitor0.8105
CYP450 2C9 substrateNon-substrate0.7608
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.7529
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.6907
CYP450 2D6 inhibitorNon-inhibitor0.9731
CYP450 2C19 inhibitorNon-inhibitor0.8725
CYP450 3A4 inhibitorNon-inhibitor0.8587
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9634
Ames testNon AMES toxic0.9326
CarcinogenicityNon-carcinogens0.8955
BiodegradationNot ready biodegradable0.9827
Rat acute toxicity2.2244 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9399
hERG inhibition (predictor II)Non-inhibitor0.5786
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
20-oxosteroids / 3-alpha-hydroxysteroids / Tertiary alcohols / Ketones / Cyclic alcohols and derivatives / Organic oxides / Hydrocarbon derivatives
Substituents
Progestogin-skeleton / 20-oxosteroid / 3-hydroxysteroid / Hydroxysteroid / 3-alpha-hydroxysteroid / Oxosteroid / Cyclic alcohol / Tertiary alcohol / Ketone / Hydrocarbon derivative
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
Molecular Weight
51801.395 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRA2
Uniprot ID
P47869
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-2
Molecular Weight
51325.85 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRA3
Uniprot ID
P34903
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-3
Molecular Weight
55164.055 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRA4
Uniprot ID
P48169
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-4
Molecular Weight
61622.645 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transporter activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRA5
Uniprot ID
P31644
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-5
Molecular Weight
52145.645 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRA6
Uniprot ID
Q16445
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-6
Molecular Weight
51023.69 Da

Drug created on October 21, 2007 16:23 / Updated on November 02, 2018 06:08