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.