6HTY
PXR in complex with P2X4 inhibitor compound 25
Summary for 6HTY
| Entry DOI | 10.2210/pdb6hty/pdb |
| Descriptor | Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1, GLYCEROL, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | pxr, src-1, cyp3a4 induction, transcription |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 79281.73 |
| Authors | Hillig, R.C.,Puetter, V.,Werner, S.,Mesch, S.,Laux-Biehlmann, A.,Braeuer, N.,Dahloef, H.,Klint, J.,ter Laak, A.,Pook, E.,Neagoe, I.,Nubbemeyer, R.,Schulz, S. (deposition date: 2018-10-05, release date: 2019-12-04, Last modification date: 2024-01-24) |
| Primary citation | Werner, S.,Mesch, S.,Hillig, R.C.,Ter Laak, A.,Klint, J.,Neagoe, I.,Laux-Biehlmann, A.,Dahllof, H.,Brauer, N.,Puetter, V.,Nubbemeyer, R.,Schulz, S.,Bairlein, M.,Zollner, T.M.,Steinmeyer, A. Discovery and Characterization of the Potent and Selective P2X4 InhibitorN-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure-Guided Amelioration of Its CYP3A4 Induction Profile. J.Med.Chem., 62:11194-11217, 2019 Cited by PubMed Abstract: The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types, especially those involved in inflammatory and immune processes. High-throughput screening led to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased pregnane X receptor (PXR) binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP 3A4 induction for compounds and . Unfortunately, the in vivo pharmacokinetic (PK) profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 () was identified and characterized as a potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, and the anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse complete Freund's adjuvant (CFA) inflammatory pain model. PubMed: 31746599DOI: 10.1021/acs.jmedchem.9b01304 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.22 Å) |
Structure validation
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