5NFT

Glucocorticoid Receptor in complex with AZD5423

5NFT の概要

• エントリーDOI: 10.2210/pdb5nft/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: glucocorticoid receptor, nuclear hormone receptor, steroid receptor, ligand complex, peptide complex, hormone
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Isoform Alpha: Cytoplasm . Isoform Beta: Nucleus . Isoform Alpha-B: Nucleus : P04150; Nucleus: Q15596
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34412.55

構造登録者

Edman, K.,Wissler, L. (登録日: 2017-03-15, 公開日: 2017-10-04, 最終更新日: 2024-01-17)

主引用文献

Hemmerling, M.,Nilsson, S.,Edman, K.,Eirefelt, S.,Russell, W.,Hendrickx, R.,Johnsson, E.,Karrman Mardh, C.,Berger, M.,Rehwinkel, H.,Abrahamsson, A.,Dahmen, J.,Eriksson, A.R.,Gabos, B.,Henriksson, K.,Hossain, N.,Ivanova, S.,Jansson, A.H.,Jensen, T.J.,Jerre, A.,Johansson, H.,Klingstedt, T.,Lepisto, M.,Lindsjo, M.,Mile, I.,Nikitidis, G.,Steele, J.,Tehler, U.,Wissler, L.,Hansson, T.
Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases.
J. Med. Chem., 60:8591-8605, 2017

PubMed Abstract: A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

PubMed: 28937774
DOI: 10.1021/acs.jmedchem.7b01215

実験手法

X-RAY DIFFRACTION (2.3 Å)