2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2020 Jan 1;28(1):115178. doi: 10.1016/j.bmc.2019.115178.
Ce Yi 1,  Gang Xing 1,  Siqi Wang 2,  Xiaoran Li 2,  Yichuang Liu 1,  Jinyan Li 1,  Bin Lin 1,  Anthony Yiu-Ho Woo 2,  Yuyang Zhang 2,  Li Pan 3,  Maosheng Cheng 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Department of Pharmacology, School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 31753798 DOI: 10.1016/j.bmc.2019.115178
Abstract

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.

Keywords

Asthma; COPD; Isoprenaline; Olodaterol; Salmeterol; β(2)-adrenoceptor agonist.

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