6S41
CRYSTAL STRUCTURE OF PXR IN COMPLEX WITH XPC-7455
Summary for 6S41
| Entry DOI | 10.2210/pdb6s41/pdb |
| Descriptor | 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) |
| Functional Keywords | pregnane x receptor, nuclear receptor, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 74514.62 |
| Authors | Focken, T.,Maskos, K.,Griessner, A.,Krapp, S. (deposition date: 2019-06-26, release date: 2019-10-02, Last modification date: 2024-05-15) |
| Primary citation | 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 Cited by 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: 31525968DOI: 10.1021/acs.jmedchem.9b01032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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