| Literature DB >> 28937774 |
Martin Hemmerling1, Stinabritt Nilsson2, Karl Edman3, Stefan Eirefelt2, Wayne Russell2, Ramon Hendrickx1, Eskil Johnsson1, Carina Kärrman Mårdh1, Markus Berger4, Hartmut Rehwinkel4, Anna Abrahamsson1, Jan Dahmén2, Anders R Eriksson1, Balint Gabos2, Krister Henriksson2, Nafizal Hossain2, Svetlana Ivanova2, Anne-Helene Jansson2, Tina J Jensen1, Anders Jerre2, Henrik Johansson2, Tomas Klingstedt2, Matti Lepistö1, Martin Lindsjö5, Irene Mile2, Grigorios Nikitidis2, John Steele1, Ulrika Tehler5, Lisa Wissler3, Thomas Hansson1.
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.Entities:
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Year: 2017 PMID： 28937774 DOI： 10.1021/acs.jmedchem.7b01215
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446