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Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy

Nonselective antagonists of voltage-gated sodium (NaV) 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 NaV1.6 and NaV1.2. However, these currently marketed drugs require hi...

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Published in:Journal of medicinal chemistry 2019-11, Vol.62 (21), p.9618-9641
Main Authors: Focken, Thilo, Burford, Kristen, Grimwood, Michael E, Zenova, Alla, Andrez, Jean-Christophe, Gong, Wei, Wilson, Michael, Taron, Matt, Decker, Shannon, Lofstrand, Verner, Chowdhury, Sultan, Shuart, Noah, Lin, Sophia, Goodchild, Samuel J, Young, Clint, Soriano, Maegan, Tari, Parisa K, Waldbrook, Matthew, Nelkenbrecher, Karen, Kwan, Rainbow, Lindgren, Andrea, de Boer, Gina, Lee, Stephanie, Sojo, Luis, DeVita, Robert J, Cohen, Charles J, Wesolowski, Steven S, Johnson, J. P, Dehnhardt, Christoph M, Empfield, James R
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container_end_page 9641
container_issue 21
container_start_page 9618
container_title Journal of medicinal chemistry
container_volume 62
creator Focken, Thilo
Burford, Kristen
Grimwood, Michael E
Zenova, Alla
Andrez, Jean-Christophe
Gong, Wei
Wilson, Michael
Taron, Matt
Decker, Shannon
Lofstrand, Verner
Chowdhury, Sultan
Shuart, Noah
Lin, Sophia
Goodchild, Samuel J
Young, Clint
Soriano, Maegan
Tari, Parisa K
Waldbrook, Matthew
Nelkenbrecher, Karen
Kwan, Rainbow
Lindgren, Andrea
de Boer, Gina
Lee, Stephanie
Sojo, Luis
DeVita, Robert J
Cohen, Charles J
Wesolowski, Steven S
Johnson, J. P
Dehnhardt, Christoph M
Empfield, James R
description Nonselective antagonists of voltage-gated sodium (NaV) 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 NaV1.6 and NaV1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of NaV1.6, while sparing NaV1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of NaV1.2 may complement the anticonvulsant activity of NaV1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective NaV1.6 inhibitors, which also displayed potent block of NaV1.2. Optimization focused on increasing selectivity over NaV1.1, 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.
doi_str_mv 10.1021/acs.jmedchem.9b01032
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title Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy
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