Discovery of N-Aryloxypropylbenzylamines as Voltage-gated Sodium Channel NaV1.2 subtype Selective Inhibitors.

We previously reported that a lipophilic derivative (1) of the voltage-gated sodium channel blocker mexiletine, prepared by coupling di-tert-butyl-phenol to mexiletine via a linker, was a more potent sodium channel blocker in vitro and in vivo. We demonstrate that replacing the methylethylene linker between the amine and di-tert-butyl-phenol with an achiral propylene linker (to give (2)) maintains potency in vitro. We synthesised 25 analogues bearing the propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1.2 and 1.6 channels by high throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV1.2 inhibitors and >500 times less potent in inhibiting NaV1.6 channels. On the other hand, a dimethoxy derivative (4) was the most potent inhibitor but is non-selective against both channels in the tonic, frequency-dependent and inactivated states. In a kindled mouse model of refractory epilepsy compound 2 inhibited seizures induced by 6 Hz 44 mA electrical stimulation with an IC50 value of 49.9 ± 1.6 mg/kg. As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco-resistant epilepsy.