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

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.
Authors	Martin Hemmerling, Stinabritt Nilsson, Karl Edman, Stefan Eirefelt, Wayne Russell, Ramon Hendrickx, Eskil Johnsson, Carina Kärrman Mårdh, Markus Berger, Hartmut Rehwinkel, Anna Abrahamsson, Jan Dahmén, Anders R Eriksson, Balint Gabos, Krister Henriksson, Nafizal Hossain, Svetlana Ivanova, Anne-Helene Jansson, Tina J Jensen, Anders Jerre, Henrik Johansson, Tomas Klingstedt, Matti Lepistö, Martin Lindsjö, Irene Mile, Grigorios Nikitidis, John Steele, Ulrika Tehler, Lisa Wissler, Thomas Hansson
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 20 Pg. 8591-8605 (10 26 2017) ISSN: 1520-4804 [Electronic] United States
PMID	28937774 (Publication Type: Journal Article)
Chemical References	2,2,2-trifluoro-N-(1-((1-(4-fluorophenyl)-1H-indazol-5-yl)oxy)-1-(3-methoxyphenyl)-2-propanyl)acetamide Acetamides Indazoles Powders Receptors, Glucocorticoid
Topics	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)

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