Abstracts

Rationale: Seizure disorders represent a significant unmet medical need. Despite >22 anticonvulsant drugs on the market, it is estimated that at least 25-40% of epilepsy patients remain resistant to current therapy and continue to have seizures (Schmidt and Sillanpaa et al, 2012). GABA_A receptors (GABA_AR) regulate neuronal excitability and are thus targets of interest for therapeutic intervention in seizure disorders. In fact, the most common first line therapies for acute seizure control are benzodiazepines, which positively modulate GABA_A receptors. However, benzodiazepine resistance is a feature of certain seizure disorders such as status epilepticus (SE) and in addition, tolerance to benzodiazepines is a common phenomenon. For example, Benzodiazepines are ineffective in approximately 30% of SE patients (Silbergleit et al, 2012). As they bind to the interface of the α and γ subunits, a population of GABA_A receptors remain unaffected by benzodiazepines including extra-synaptic δ-subunit containing receptors. Therefor, novel therapies that target a broader population of GABA_A receptors may provide improved anticonvulsant efficacy in seizure disorders. Neuroactive steroids (NAS) are a class of endogenous and synthetic positive allosteric modulators (PAMs) that target both synaptic and extrasynaptic GABA_A receptors and have demonstrated anticonvulsant effects in multiple preclinical models (Rogawski et al. 2013). However, NAS have historically been challenged by low oral bioavailability and rapid clearance. In order to address these limitations, we have generated multiple novel series of synthetic neuroactive steroids with improved pharmacokinetic profiles. Methods: Here we report the in vitro electrophysiological potency of a novel series of Neuroactive Steroid (NAS) drug candidates at both a1b2g2 and a4b3d GABA_ARs. In addition, we have measured the pharmacokinetic properties and brain exposure of key examples in rodents by iv and oral administration. Finally, we have characterized the efficacy of these selected candidates in rodent models of seizure (inhibition of PTZ-induced seizures). Results: Through a medicinal chemistry structure activity relationship (SAR) campaign we have optimized our lead series of neuroactive steroids for both potency at GABA_A receptor subtypes as well as pharmacokinetic properties to allow for identification of bioavailable drug candidates as potential therapeutics for epilepsy indications. Conclusions: The identification of orally bioavailable novel neuroactive steroids was accomplished through a medicinal chemistry SAR campaign. Several promising candidates showed excellent efficacy in rodent models of seizure demonstrating their potential as effective treatments for epilepsy in humans.