| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
GABAA-alpha5 receptor (specifically the alpha5beta3gamma2 subunit). Alogabat is a potent positive allosteric modulator (PAM) of GABAA-alpha5 receptors, with a Ki of 8.7 nM for the alpha5beta3gamma2 subunit. It has binding and functional selectivity for the alpha5 subtype, which is key for its cognitive effects versus the sedative or anxiolytic effects of alpha1-preferring modulators.
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|---|---|
| ln Vitro |
In vitro, Alogabat exhibits high-affinity binding to recombinant human GABAA-alpha5beta3gamma2 receptors with a Ki of 8.7 nM. As a PAM, it allosterically potentiates the effect of GABA at the alpha5-containing receptor. It shows binding and functional selectivity for the alpha5 subunit, making it distinct from non-selective GABAA modulators like diazepam.
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| ln Vivo |
In vivo, Alogabat shows beneficial effects in mouse models relevant for neurodevelopmental disorders (NDD), as well as anti-seizure activity. It normalizes elevated self-grooming behavior in both Cntnap2-/- and BTBR mouse models of autism at doses without cognitive, sedative, or motoric side effects. Receptor occupancy studies provide direct proof of dose-dependent target engagement.
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| Enzyme Assay |
A standard non-cellular protocol for Alogabat is a radioligand binding assay. HEK-293 cell membranes expressing the GABAA-alpha5beta3gamma2 receptor are incubated with [3H]flumazenil (a non-selective benzodiazepine site antagonist) and varying concentrations of Alogabat to determine its affinity for the benzodiazepine site on the alpha5 subunit. A competition for the [3H]flumazenil binding will be observed.
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| Cell Assay |
The functional cellular activity for Alogabat is studied using electrophysiological assays. Xenopus oocytes or HEK-293 cells expressing the GABAA-alpha5beta3gamma2 receptor are used in a whole-cell patch-clamp recording. A submaximal concentration of GABA is applied, followed by co-application of Alogabat. An increase in the chloride current amplitude indicates positive allosteric modulation.
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| Animal Protocol |
In a standard in vivo protocol, Alogabat is formulated in a vehicle and administered orally to rodents (e.g., C57BL/6J mice). For efficacy studies, doses of 1, 3, and 10 mg/kg are used 60 min prior to behavioral testing (e.g., marble burying or self-grooming). For PK/PD, brain and plasma are collected at various times to measure drug levels and to conduct ex vivo receptor occupancy assays.
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| ADME/Pharmacokinetics |
Specific PK data for Alogabat is not provided, but it is described as an “orally active” compound that reaches the CNS. Clinical PK studies are ongoing in pediatric populations for the treatment of Angelman Syndrome. The compound has a sufficient half-life and brain penetration to allow for once- or twice-daily dosing in preclinical species.
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| Toxicity/Toxicokinetics |
No detailed preclinical toxicology is provided, but Alogabat has entered human clinical trials. A key feature is its absence of cognitive, sedative, and motoric side effects at pharmacologically active doses, which is a major safety advantage over non-selective GABAA modulators (which cause sedation) and alpha5-inverse agonists (which can impair cognition).
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| References | |
| Additional Infomation |
See also: Fenobam Anhydrous (related).
Alogabat has been in clinical development for the treatment of Angelman Syndrome, a severe neurodevelopmental disorder caused by the loss of function of the UBE3A gene. The therapeutic hypothesis is that enhancing alpha5-GABAA signaling can compensate for the synaptic dysfunction characteristic of AS. It has received orphan drug and fast track designations from the FDA. |
| Molecular Formula |
C21H23N5O4
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|---|---|
| Molecular Weight |
409.4384
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| Exact Mass |
409.175
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| CAS # |
2230009-48-8
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| PubChem CID |
134588268
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| Appearance |
White to off-white solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
|
| Complexity |
562
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O1C([H])([H])C([H])([H])C([H])(C([H])([H])C1([H])[H])N([H])C(C1C([H])=C([H])C(=NN=1)OC([H])([H])C1=C(C([H])([H])[H])ON=C1C1=C([H])N=C(C([H])([H])[H])C([H])=C1[H])=O
|
| InChi Key |
ACZCJTHHWMBFKC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C21H23N5O4/c1-13-3-4-15(11-22-13)20-17(14(2)30-26-20)12-29-19-6-5-18(24-25-19)21(27)23-16-7-9-28-10-8-16/h3-6,11,16H,7-10,12H2,1-2H3,(H,23,27)
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| Chemical Name |
6-[[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy]-N-(oxan-4-yl)pyridazine-3-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 33.33 mg/mL (81.40 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4424 mL | 12.2118 mL | 24.4236 mL | |
| 5 mM | 0.4885 mL | 2.4424 mL | 4.8847 mL | |
| 10 mM | 0.2442 mL | 1.2212 mL | 2.4424 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT05630066
Conditions:Angelman SyndromeLink: https://clinicaltrials.gov/ct2/show/NCT04299464
Conditions:Autism Spectrum Disorder (ASD)Link: https://clinicaltrials.gov/ct2/show/NCT03847987
Conditions:Healthy Volunteers
Title:A Study to Investigate the Effect of CYP3A Inhibition on the Pharmacokinetics of RO7017773 in Healthy Participants
Status:Completed
updateDate:2020-05-07
Ctid:NCT03774576
Link: https://clinicaltrials.gov/ct2/show/NCT03774576
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT03507569
Conditions:Autism Spectrum DisorderProducts are for research use only; We do not sell to patients
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