AI Article Synopsis
- Researchers created a new class of nonsteroidal drugs called selective indazole ether-based glucocorticoid receptor modulators (SGRMs) specifically for inhaled treatments of respiratory diseases.
- They used a "soft-drug strategy" to ensure that the drugs are quickly eliminated from the body, minimizing unwanted systemic effects.
- The promising candidates, AZD5423 and AZD7594, showed effective anti-inflammatory results in animal models and outperformed traditional inhaled corticosteroids, suggesting they could allow for once-daily dosing.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.7b01215 | DOI Listing |
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