Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β2-adrenoceptor agonists

[Display omitted] •(R)-18a (R)-18c and (R)-18f exhibited the most potent with EC50 values of 9.1 pM 24 pM and 16 pM, respectively.•(R)-18c were worthy of further investigation as a lead compound for the development of β2-adrenoceptor agonists. A series of β2-adrenoceptor agonists with an 8-(2-amino-...

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Veröffentlicht in:Bioorganic & medicinal chemistry 2020-01, Vol.28 (1), p.115178, Article 115178
Hauptverfasser: Yi, Ce, Xing, Gang, Wang, Siqi, Li, Xiaoran, Liu, Yichuang, Li, Jinyan, Lin, Bin, Woo, Anthony Yiu-Ho, Zhang, Yuyang, Pan, Li, Cheng, Maosheng
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Sprache:eng
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Zusammenfassung:[Display omitted] •(R)-18a (R)-18c and (R)-18f exhibited the most potent with EC50 values of 9.1 pM 24 pM and 16 pM, respectively.•(R)-18c were worthy of further investigation as a lead compound for the development of β2-adrenoceptor agonists. A series of β2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β2-adrenoceptor and β1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β2-adrenoceptor agonistic effect with an EC50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β2-AR agonists.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.115178