Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective Na V 1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.

Autor:	Focken T; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Burford K; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Grimwood ME; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Zenova A; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Andrez JC; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Gong W; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Wilson M; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Taron M; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Decker S; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Lofstrand V; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Chowdhury S; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Shuart N; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Lin S; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Goodchild SJ; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Young C; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Soriano M; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Tari PK; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Waldbrook M; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Nelkenbrecher K; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Kwan R; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Lindgren A; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., de Boer G; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Lee S; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Sojo L; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., DeVita RJ; RJD Medicinal Chemistry and Drug Discovery Consulting LLC , Westfield , New Jersey 07090 , United States., Cohen CJ; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Wesolowski SS; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Johnson JP Jr; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Dehnhardt CM; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada., Empfield JR; Xenon Pharmaceuticals Inc. , 200-3650 Gilmore Way , Burnaby , British Columbia V5G 4W8 , Canada.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Nov 14; Vol. 62 (21), pp. 9618-9641. Date of Electronic Publication: 2019 Oct 03.
DOI:	10.1021/acs.jmedchem.9b01032
Abstrakt:	Nonselective antagonists of voltage-gated sodium (Na V ) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily Na V 1.6 and Na V 1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na V 1.6, while sparing Na V 1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na V 1.2 may complement the anticonvulsant activity of Na V 1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na V 1.6 inhibitors, which also displayed potent block of Na V 1.2. Optimization focused on increasing selectivity over Na V 1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30-32 , which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.
Databáze:	MEDLINE
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