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| Targets |
The primary targets are AMPA‑type glutamate receptors (AMPARs) and kainate‑type glutamate receptors (KARs). For AMPAR, the IC₅₀ is 190 nM, and the functional efficacy (IC₅₀) on native AMPA receptors in rat cortical wedges is 0.46 µM.
For KAR, the functional efficacy (IC₅₀) on native kainate receptors in rat cortical wedges is 0.42 µM. For NMDA receptors, the functional efficacy is >30 µM, indicating little affinity. No Ki or EC₅₀ values were reported. [2] |
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| ln Vitro |
Selurampanel is a competitive AMPAR antagonist that binds within the glutamate cleft of the extracellular domain of the receptor, blocking the clamshell‑like closure necessary for pore opening, as demonstrated crystallographically for the GluA2 tetramer.
It has an IC₅₀ of 190 nM for the AMPAR and also shows antagonist activity at KAR sites. The compound is quite selective for AMPARs and KARs, with little affinity for NMDA receptors (functional efficacy >30 µM for NMDA). The IC₅₀ for 150 other molecular targets was >10 µM, suggesting a low likelihood of unwanted central nervous system effects. It acts by directly competing with glutamate for the receptor binding site, unlike noncompetitive antagonists that bind to allosteric sites. [2] |
| ln Vivo |
Selurampanel (Compound 1S) efficiently and dose-dependently inhibits generalized tonic-clonic seizures caused by maximal electroshock seizure (MES) in mice, with an ED50 value of about 7 mg/kg after 1 hour of pretreatment [1]. The mouse plasma half-life was found to be 3.3 hours in a research involving an intravenous dosage of 3 mg/kg. It also had a low clearance of 5.4 mL/min▯kg and a medium volume of distribution (Vdss=1.3 L/kg).
In the mouse maximal electroshock seizure (MES) model, Selurampanel showed an oral ED₅₀ of 6 mg/kg. It was also effective in the DBA/2 audiogenic seizure mouse model, the pentylenetetrazole‑induced seizure model, and the WAG/Rij rat model (which is predictive of anti‑absence activity). Efficacy against kindling suggests potential action against human complex partial (dyscognitive) seizures. In a photosensitive epilepsy trial (single doses of 15, 50, and 100 mg), 9 out of 13 subjects had complete suppression of the photoparoxysmal response (PPR) for 2 to 32 hours, with some reduction in all actively treated subjects. In an inpatient presurgical trial (75 or 150 mg/day in three divided doses for 9 days), Selurampanel reduced seizure rate by about 50% compared to placebo (drug 0.59/day, 90% CI: 0.35‑1.02 vs placebo 1.22/day, 90% CI: 0.73‑2.04). Complex partial seizures were reduced comparatively more than secondarily generalized tonic‑clonic seizures. In a 12‑week double‑blind adjunctive therapy trial for refractory partial‑onset seizures (300 and 450 mg/day), the mean percentage change from baseline was 39% for 450 mg/day (n=44), 22% for 300 mg/day (n=24), and 24% for placebo (n=25). Median percentage changes were 30% (450 mg/day), 33.4% (300 mg/day), and 14.3% (placebo). The primary endpoint did not reach statistical significance (adjusted p values 0.083‑0.099). In an open‑label extension (up to 30 weeks), responder rates (≥50% seizure reduction) reached 46% during weeks 14‑26. [2] |
| Enzyme Assay |
Radioligand binding assays were performed using rat whole‑brain membranes. [³H]CNQX was used to assess affinity at the AMPA receptor; [³H]HCGP39653 and [³H]HMDL105519 were used for NMDA receptor glutamate and glycine sites, respectively; [³H]kainate was used for kainate receptor binding. IC₅₀ values were calculated using GraphPad Prism software. Data are geometric means of at least three independent experiments. [1]
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| Cell Assay |
(1) hERG cell‑based assay: Selurampanel showed an IC₅₀ > 30 μM, indicating low risk of hERG interaction. [1]
(2) CYP450 inhibition assay: Selurampanel showed no substantial inhibition of all tested cytochrome P450 isoforms up to 10 μM. [1] |
| Animal Protocol |
Preclinical efficacy studies were conducted in mouse models including the maximal electroshock seizure (MES) model, the DBA/2 audiogenic seizure model, the pentylenetetrazole‑induced seizure model, and the WAG/Rij rat model. In the MES model, the oral ED₅₀ was determined to be 6 mg/kg. Details on formulation, administration route, and dosing volume were not provided in this review. [2]
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| ADME/Pharmacokinetics |
Preclinical data showed considerable interspecies differences in oral absorption, clearance, and volume of distribution, although a rapid Tₘₐₓ of 0.5‑1 hour was observed in three different species.
Protein binding in mammals was moderate, ranging from 75‑88%. No cytochrome P450 induction or inhibition was observed. In humans, after a single dose, Tₘₐₓ was about 3 hours (measured in the photosensitive epilepsy study). Drug exposure versus dose was relatively linear for doses of 15, 50, and 100 mg. During the inpatient trial (after 3, 6, and 9 days of treatment), Tₘₐₓ ranged from 1.25 to 3.22 hours, and the area under the curve (AUC) was linear; exposure to a 50 mg morning dose was approximately double that of a 25 mg morning dose. Oral bioavailability is reported to be good, with reasonable blood‑brain barrier penetration. [2] |
| Toxicity/Toxicokinetics |
Preclinical safety studies showed no indication of cardiotoxicity, reproductive toxicity, or genotoxicity, and no protein adduct formation occurred.
In clinical trials, the most common treatment‑emergent adverse effects were dizziness and somnolence. In the 12‑week double‑blind study, dizziness occurred in 31.8% (450 mg/day), 12.5% (300 mg/day), and 4.0% (placebo); somnolence occurred in 15.9% (450 mg/day), 4.2% (300 mg/day), and 4.0% (placebo). Fatigue, confusion, vertigo, and gait disturbance were also reported at lower rates. Discontinuation rates in the 10‑week outpatient trial were 15.9% (450 mg/day), 16.7% (300 mg/day), and 4% (placebo). In the open‑label extension, 15.7% dropped out, with 5.9% attributed to adverse events. No deaths were reported among 110 clinical trial participants. No serious adverse events were reported in the short‑term trials; one SAE (nature unspecified) occurred in the open‑label phase. No rashes or allergic reactions were reported. One patient discontinued the 450 mg/day dose due to irritability; psychiatric disorders were reported in 5.9% of open‑label patients. No cardiotoxicity, reproductive toxicity, or genotoxicity signals were observed in preclinical studies. [2] |
| References | |
| Additional Infomation |
Selurampanel has been studied in adrenocortical adenomas and sarcomas, and endometrial stromal tumors.
Selurampanel (BGG492, CAS# 912574‑69‑7) is a competitive AMPA/kainate receptor antagonist under development for epilepsy. It is a quinazolinedione sulfonamide derivative with good oral bioavailability and reasonable blood‑brain barrier penetration. The compound has been studied in Phase II clinical trials for photosensitive epilepsy, presurgical evaluation of partial seizures, and as adjunctive therapy for refractory partial‑onset seizures. The mechanism involves binding within the glutamate cleft of the AMPA receptor extracellular domain, blocking the conformational change required for ion channel opening. It also has antagonist activity at kainate receptors, though the relevance to antiepileptic effect is unknown. In clinical trials, the drug was administered orally at doses ranging from 15 mg to 450 mg per day, typically in divided doses (e.g., three times daily). Efficacy was modest, with median seizure reduction of 30‑33.4% at higher doses versus 14.3% for placebo in one trial, though the primary endpoint was not met. The most common adverse effects are dizziness and somnolence, typical of AMPAR antagonists. Tolerability appears reasonably good, with discontinuation rates similar to other antiepileptic drugs. The drug has not been approved; development may be limited due to the availability of perampanel (a noncompetitive AMPAR antagonist) and modest efficacy signals. No FDA warnings or clinical use information are mentioned. [2] |
| Molecular Formula |
C16H19N5O4S
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|---|---|
| Molecular Weight |
377.41816
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| Exact Mass |
377.115
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| CAS # |
912574-69-7
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| PubChem CID |
45381907
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| Appearance |
White to off-white solid powder
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| LogP |
1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
677
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MCECSFFXUPEPDB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H19N5O4S/c1-9(2)10-8-13-12(7-11(10)14-5-6-17-20(14)3)15(22)21(16(23)18-13)19-26(4,24)25/h5-9,19H,1-4H3,(H,18,23)
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| Chemical Name |
N-[6-(2-methylpyrazol-3-yl)-2,4-dioxo-7-propan-2-yl-1H-quinazolin-3-yl]methanesulfonamide
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| Synonyms |
BGG492 BGG-492 BGG 492
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6496 mL | 13.2478 mL | 26.4957 mL | |
| 5 mM | 0.5299 mL | 2.6496 mL | 5.2991 mL | |
| 10 mM | 0.2650 mL | 1.3248 mL | 2.6496 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00784212 | COMPLETED | Drug: BGG492 Drug: BGG492 Drug: Placebo |
Photosensitive Epilepsy | Novartis Pharmaceuticals | 2008-10 | Phase 2 |
| NCT01338805 | COMPLETED | Drug: BGG492 | Partial Onset Seizures | Novartis Pharmaceuticals | 2011-06 | Phase 2 |
| NCT01649050 | WITHDRAWN | Drug: BGG492 Drug: Placebo |
Muscle Spasticity Due to Multiple Sclerosis | Novartis Pharmaceuticals | 2016-10 | Phase 2 |
| NCT01167335 | WITHDRAWN | Drug: BGG492 Drug: Placebo |
Partial Onset Seizures | Novartis | 2010-08 | Phase 2 |
| NCT00892203 | COMPLETED | Drug: BGG492 Drug: Sumatriptan Drug: Placebo |
Migraine | Novartis | 2009-04 | Phase 2 |
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