5NFP

Glucocorticoid Receptor in complex with budesonide

Summary for 5NFP

• Entry DOI: 10.2210/pdb5nfp/pdb
• Descriptor: Glucocorticoid receptor, Nuclear receptor coactivator 2, 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE, ... (7 entities in total)
• Functional Keywords: glucocorticoid receptor, nuclear hormone receptor, steroid receptor, ligand complex, peptide complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform Alpha: Cytoplasm . Isoform Beta: Nucleus . Isoform Alpha-B: Nucleus : P04150; Nucleus: Q15596
• Total number of polymer chains: 2
• Total formula weight: 35095.64

Authors

Edman, K.,Wissler, L. (deposition date: 2017-03-15, release date: 2017-10-04, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)