Design and optimization of 5-hydroxy-4H-benzo[1,4]oxazin-3-one-derived β₂-adrenoceptor agonists with potent anti-asthmatic activity.

Authors

Lanyan Ma, Zhengxing Zhi, Zhenli Li, Li Pan, Yin Sun, Yang Liu, Maosheng Cheng, Gang Xing

Published in

European journal of medicinal chemistry. Volume 319. Pages 119297. Sep 02, 2026. Epub Sep 02, 2026.

Abstract

β₂-Adrenergic receptor (β₂-AR) agonists, as classic bronchodilators, serve as the cornerstone for asthma treatment. Herein, we designed and synthesized a series of derivatives based on the 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold. Based on a comprehensive evaluation of four core indicators, including cAMP accumulation assays in HEK293 cells overexpressing human β₂-AR or β₁-AR, guinea pig tracheal strip assays, and in vitro cytotoxicity, compound C3 exhibited the best overall performance (β₂-AR EC₅₀ = 7 pM, β₂/β₁ selectivity > 97-fold; isolated tracheal relaxation E_max = 136.88, pD₂ = 8.32; human bronchial epithelial cell BEAS-2B CC₅₀ = 50.07 μM) and was selected as the candidate molecule. In a mouse asthma model, C3 administered at 200 μg/kg/day (458.5 nmol/kg/day) markedly suppressed inflammatory cell activity and improved lung function, showing anti-asthmatic efficacy comparable to that of salmeterol at 300 μg/kg/day (721.7 nmol/kg/day). In conclusion, C3 is a β₂-AR agonist with potential application value, holding promise for the treatment of asthma.

PMID:
42702173
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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