6S41

CRYSTAL STRUCTURE OF PXR IN COMPLEX WITH XPC-7455

6S41 の概要

• エントリーDOI: 10.2210/pdb6s41/pdb
• 分子名称: Nuclear receptor subfamily 1 group I member 2, 4-[[(1~{S})-1-[2,5-bis(fluoranyl)phenyl]ethyl]amino]-5-chloranyl-2-fluoranyl-~{N}-(1,3-thiazol-4-yl)benzenesulfonamide (3 entities in total)
• 機能のキーワード: pregnane x receptor, nuclear receptor, nuclear protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 74514.62

構造登録者

Focken, T.,Maskos, K.,Griessner, A.,Krapp, S. (登録日: 2019-06-26, 公開日: 2019-10-02, 最終更新日: 2024-05-15)

主引用文献

Focken, T.,Burford, K.,Grimwood, M.E.,Zenova, A.,Andrez, J.C.,Gong, W.,Wilson, M.,Taron, M.,Decker, S.,Lofstrand, V.,Chowdhury, S.,Shuart, N.,Lin, S.,Goodchild, S.J.,Young, C.,Soriano, M.,Tari, P.K.,Waldbrook, M.,Nelkenbrecher, K.,Kwan, R.,Lindgren, A.,de Boer, G.,Lee, S.,Sojo, L.,DeVita, R.J.,Cohen, C.J.,Wesolowski, S.S.,Johnson Jr., J.P.,Dehnhardt, C.M.,Empfield, J.R.
Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.
J.Med.Chem., 62:9618-9641, 2019

PubMed Abstract: Nonselective antagonists of voltage-gated sodium (Na) 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 Na1.6 and Na1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of Na1.6, while sparing Na1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of Na1.2 may complement the anticonvulsant activity of Na1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective Na1.6 inhibitors, which also displayed potent block of Na1.2. Optimization focused on increasing selectivity over Na1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds , which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.

PubMed: 31525968
DOI: 10.1021/acs.jmedchem.9b01032

実験手法

X-RAY DIFFRACTION (2.7 Å)