6s41 | pdb_00006s41
CRYSTAL STRUCTURE OF PXR IN COMPLEX WITH XPC-7455
Structural highlights
Function[NR1I2_HUMAN] Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedNonselective 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 PXR (pregnane X-receptor) liability. We obtained compounds 30-32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock (DC-MES) seizure assay. Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.,Focken T, Burford K, Grimwood ME, Zenova A, Andrez JC, Gong W, Wilson M, Taron M, Decker S, Lofstrand V, Chowdhury S, Shuart N, Lin S, Goodchild SJ, Young C, Soriano M, Tari PK, Waldbrook M, Nelkenbrecher K, Kwan R, Lindgren A, de Boer G, Lee S, Sojo L, Devita RJ, Cohen CJ, Wesolowski SS, Johnson JP, Dehnhardt CM, Empfield JR J Med Chem. 2019 Sep 17. doi: 10.1021/acs.jmedchem.9b01032. PMID:31525968[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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