Non-selective blockers of voltage-gated sodium channels (NaV) are the standard treatment option for many epileptic disorders despite their often dose limiting side-effects. Adult Central Nervous System (CNS) neurons primarily express three sodium channel isoforms: NaV1.1, NaV1.2, and NaV1.6. NaV1.1 is the dominant isoform in inhibitory interneurons, whereas NaV1.2 and NaV1.6 are responsible for initiation and propagation of signaling in excitatory glutamergic neurons. An imbalance in the excitatory/inhibitory neurons caused by abnormal expression or function of NaV’s contributes to the pathophysiology of epilepsy. It is believed that block of NaV1.1 is counter-productive since genetic loss-of-function of this channel leads to seizures. On the other hand, block of NaV’s expressed in excitatory neurons, in particular NaV1.6, can be linked to anticonvulsant activity. In this talk, we discuss the multi-parameter optimization and in vivo studies of brain penetrant selective dual NaV1.6/1.2 inhibitors with high selectivity over NaV1.1 and good CNS exposure. Besides balancing potency, microsomal stability, and brain exposure, we strived to minimize DDI risk by reducing PXR. Furthermore, using small molecule X-ray crystal structures in conjunction with molecular modeling guided compound design to optimize potency and CNS exposure. We also report on the ability of these novel inhibitors to prevent seizures in the highly validated maximal electroshock seizure (MES) test in mice.

Multi-parameter optimization of isoform-selective dual NaV1.6/1.2 antagonists to balance CNS penetration with PK and in vivo efficacy in mouse models for epilepsy

2019 Spring National Meeting

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