Rationale:
Anxiety diminishes quality of life in epilepsy beyond the impact of seizure frequency alone (Johnson et al., 2004), contributes to suicidality (Christensen et al., 2007), and is more prevalent in drug‑resistant epilepsy (DRE) (Nogueira et al., 2017; Lu et al., 2021; Gavrilovic et al., 2024), where stakes are highest. A therapy that reduces both seizures and anxiety could yield meaningful gains in quality of life, bolster adherence, and potentially lower healthcare utilization—outcomes not addressed by seizure‑only standard‑of‑care (SOC) (Gandy et al., 2021; Munger Clary et al., 2024). Sensorium therapeutics has developed a novel anti-epileptic with anxiolytic properties, to address an unmet need in patients with epilepsy (PWE)
Methods:
SNTX‑1675, a naturally occurring compound identified with Sensorium’s Sens‑AI platform, has reported human use as an anxiolytic and anti‑convulsant. We evaluated SNTX‑1675 across rodent models of seizures (6 Hz psychomotor: 22, 33, 44 mA; maximal electroshock seizure [MES]; corneal kindling) and anxiety‑related behavior (marble‑burying), with rotarod to assess motor impairment. Receptor‑binding and functional ion‑channel assays were used to profile pharmacological targets potentially underlying efficacy. A medicinal chemistry campaign using traditional SAR generated SNTX‑EA, a synthetic derivative optimized for CNS drug‑like properties. In vitro and in vivo pharmacokinetic (PK) studies compared SNTX‑EA with the parent scaffold.
Results:
SNTX‑1675 demonstrated anti‑seizure efficacy in the 6 Hz 22 mA and 33 mA assays and in corneal kindling, consistent with reported human use. It also showed anxiolytic‑like effects in marble‑burying without rotarod impairment. Guided by these readouts, optimization produced SNTX‑EA, which retained efficacy at 6 Hz 33 mA and in corneal kindling and additionally exhibited activity in a pharmacoresistant model (6 Hz 44 mA) and in MES. PK profiling indicated improved CNS drug‑like characteristics for SNTX‑EA versus SNTX‑1675 in vitro, corroborated by enhanced in vivo exposure.
Conclusions:
SNTX‑EA is a synthetic derivative of a natural product with concordant anti‑seizure and anxiolytic‑like activity across multiple rodent models and improved CNS‑relevant PK properties. These findings support advancement of SNTX‑EA for epilepsy with comorbid anxiety—a serious unmet need not adequately addressed by seizure‑only SOC. Sensorium is advancing this molecule toward clinical development in epilepsy with comorbid anxiety.
Funding: None