6HTY

PXR in complex with P2X4 inhibitor compound 25

6HTY の概要

• エントリーDOI: 10.2210/pdb6hty/pdb
• 分子名称: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1, GLYCEROL, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: pxr, src-1, cyp3a4 induction, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79281.73

構造登録者

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. (登録日: 2018-10-05, 公開日: 2019-12-04, 最終更新日: 2024-01-24)

主引用文献

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

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: 31746599
DOI: 10.1021/acs.jmedchem.9b01304

実験手法

X-RAY DIFFRACTION (2.22 Å)