Discovery of N‐Aryloxypropylbenzylamines as Voltage‐Gated Sodium Channel Na_V1.2‐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.

Pd-Catalyzed ipso,meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C–H Activation Cascade with Dimethyl Carbonate as the Methyl Source

“…Many of the 2,6-dimethylated anisole products, such as 3f , 3g , 3h , 3i , 3k , 3l , 3o , and 3p ,, and their demethylated analogues, the 2,6-dimethylphenols, − are essential intermediates in the syntheses of biologically and pharmacologically active compounds (Figure c). Demethylation of the 2,6-dimethylanisole products was exemplified by the reactions of 3f and 3f - D (Figure b).…”

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

“…These three compounds exhibited inhibitory effects on the Na V 1.2 channel activity and showed anticonvulsant activity in vivo . Compound 10 , a mexiletine analogue, is a highly selective Na V 1.2 inhibitor that can inhibit seizures in a kindled mouse model of refractory epilepsy (6HZ 44 mA) …”

“…143 Compound 10, a mexiletine analogue, is a highly selective Na V 1.2 inhibitor that can inhibit seizures in a kindled mouse model of refractory epilepsy (6HZ 44 mA). 144 4.1.2. Potassium Channel Agonists.…”

Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy

“…Currently, various inhibitors acting on Nav1.2 have been reported (Figure ). − Elpetrigine ( 1 ), a derivative of lamotrigine, is currently undergoing evaluation as an anticonvulsant in patients. Elpetrigine demonstrated efficacy with an ED 50 value of 5.9 mg/kg in the MES test.…”