Journal article

Discovery of N-Aryloxypropylbenzylamines as Voltage-Gated Sodium Channel Na(V)1.2-Subtype-Selective Inhibitors

Phillip L van der Peet, Saman Sandanayake, Bevyn Jarrott, Spencer J Williams

CHEMMEDCHEM | WILEY-V C H VERLAG GMBH | Published : 2019

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 NaV 1.2 and 1.6 channels by high-throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective N..

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Grants

Funding Acknowledgements

We are grateful to the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) for invivo mouse studies of the antiseizure properties of compound <BOLD>2</BOLD>. We thank FastForward (USA) for project funding, and invaluable advice from Dr. John Lowe (JL3Pharma, Stonington, CT, USA).