- 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 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.
- Hemmerling, Martin,Nilsson, Stinabritt,Edman, Karl,Eirefelt, Stefan,Russell, Wayne,Hendrickx, Ramon,Johnsson, Eskil,K?rrman M?rdh, 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,Lepist?, Matti,Lindsj?, Martin,Mile, Irene,Nikitidis, Grigorios,Steele, John,Tehler, Ulrika,Wissler, Lisa,Hansson, Thomas
-
p. 8591 - 8605
(2017/11/03)
-