Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel NaV1.2‐Subtype‐Selective Inhibitors

Abstract We previously reported that a lipophilic N‐(4′‐hydroxy‐3′,5′‐di‐tert‐butylbenzyl) derivative (1) of the voltage‐gated sodium channel blocker mexiletine, was a more potent sodium channel blocker in vitro and in vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di‐tert‐butylphenol with an achiral 1,3‐propylene linker (to give (2)) maintains potency in vitro. We synthesized 25 analogues bearing the 1,3‐propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV1.2 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 derivative (compound 4) bearing 2,6‐dimethoxy groups in place of the 2,6‐dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective 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−1. 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.