TY - JOUR
T1 - Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy
AU - Focken, Thilo
AU - Burford, Kristen
AU - Grimwood, Michael E.
AU - Zenova, Alla
AU - Andrez, Jean Christophe
AU - Gong, Wei
AU - Wilson, Michael
AU - Taron, Matt
AU - Decker, Shannon
AU - Lofstrand, Verner
AU - Chowdhury, Sultan
AU - Shuart, Noah
AU - Lin, Sophia
AU - Goodchild, Samuel J.
AU - Young, Clint
AU - Soriano, Maegan
AU - Tari, Parisa K.
AU - Waldbrook, Matthew
AU - Nelkenbrecher, Karen
AU - Kwan, Rainbow
AU - Lindgren, Andrea
AU - De Boer, Gina
AU - Lee, Stephanie
AU - Sojo, Luis
AU - Devita, Robert J.
AU - Cohen, Charles J.
AU - Wesolowski, Steven S.
AU - Johnson, J. P.
AU - Dehnhardt, Christoph M.
AU - Empfield, James R.
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/11/14
Y1 - 2019/11/14
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85073450063
U2 - 10.1021/acs.jmedchem.9b01032
DO - 10.1021/acs.jmedchem.9b01032
M3 - Article
C2 - 31525968
AN - SCOPUS:85073450063
SN - 0022-2623
VL - 62
SP - 9618
EP - 9641
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -