Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

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 impleme...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2017-10, Vol.60 (20), p.8591-8605
Main Authors: Hemmerling, Martin, Nilsson, Stinabritt, Edman, Karl, Eirefelt, Stefan, Russell, Wayne, Hendrickx, Ramon, Johnsson, Eskil, Kärrman Mårdh, Carina, Berger, Markus, Rehwinkel, Hartmut, Abrahamsson, Anna, Dahmén, Jan, Eriksson, Anders R, Gabos, Balint, Henriksson, Krister, Hossain, Nafizal, Ivanova, Svetlana, Jansson, Anne-Helene, Jensen, Tina J, Jerre, Anders, Johansson, Henrik, Klingstedt, Tomas, Lepistö, Matti, Lindsjö, Martin, Mile, Irene, Nikitidis, Grigorios, Steele, John, Tehler, Ulrika, Wissler, Lisa, Hansson, Thomas
Format: Article
Language:English
Subjects:
Acetamides - therapeutic use
Administration, Inhalation
Aged
Animals
Dose-Response Relationship, Drug
Humans
Indazoles - therapeutic use
Mass Spectrometry
Powders
Proton Magnetic Resonance Spectroscopy
Pulmonary Edema - drug therapy
Rats
Receptors, Glucocorticoid - drug effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01215