5G5W

Structure guided design and discovery of Indazole ethers as highly potent, non-steroidal Glucocorticoid receptor modulators

5G5W の概要

• エントリーDOI: 10.2210/pdb5g5w/pdb
• 分子名称: GLUCOCORTICOID RECEPTOR, NUCLEAR RECEPTOR COACTIVATOR 2, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: hormone, glucocorticoid receptor, nuclear hormone receptor, steroid receptor, signaling protein, ligand complex, peptide complex
• 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: 34415.56

構造登録者

Hemmerling, M.,Edman, K.,Lepisto, M.,Eriksson, A.,Ivanova, S.,Dahmen, J.,Rehwinkel, H.,Berger, M.,Hendrickx, R.,Dearman, M.,Jellesmark-Jensen, T.,Wissler, L.,Hansson, T. (登録日: 2016-06-08, 公開日: 2017-02-15, 最終更新日: 2024-01-10)

主引用文献

Hemmerling, M.,Edman, K.,Lepisto, M.,Eriksson, A.,Ivanova, S.,Dahmen, J.,Rehwinkel, H.,Berger, M.,Hendrickx, R.,Dearman, M.,Jensen, T.J.,Wissler, L.,Hansson, T.
Discovery of Indazole Ethers as Novel, Potent, Non-Steroidal Glucocorticoid Receptor Modulators.
Bioorg.Med.Chem.Lett., 26:5741-, 2017

PubMed Abstract: A structure-based design approach led to the identification of a novel class of indazole ether based, non-steroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-α release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small sub-set of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy.

PubMed: 27810243
DOI: 10.1016/J.BMCL.2016.10.052

実験手法

X-RAY DIFFRACTION (2.2 Å)