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
复制标题
8-(2-氨基-1-羟乙基)-6-羟基-1,4-苯并恶嗪-3(4H)-1衍生物作为有效β2-肾上腺素受体激动剂的设计、合成和生物学评价
DOI：
10.1016/j.bmc.2019.115178
复制
发表时间：
2019
影响因子：
3.5
通讯作者：
Maosheng Cheng
中科院分区：
文献类型：
--
作者：
Ce Yi;Gang Xing;Siqi Wang;Xiaoran Li;Yichuang Liu;Jinyan Li;Bin Lin;Yiu-Ho Anthony Woo;Yuyang Zhang;Li Pan;Maosheng Cheng
介绍了一系列具有8-（2-氨基-1-羟乙基）-6-羟基-1,4-苯并恶嗪-3(4H)- 1片段的β2-肾上腺素受体激动剂。通过细胞实验表征了化合物对人β2-肾上腺素能受体和β1-肾上腺素能受体的刺激作用。在离体豚鼠气管上检测其平滑肌松弛活性。大多数化合物被发现是β2-肾上腺素受体的有效和选择性激动剂。其中一种化合物(R)-18c具有很强的β2-肾上腺素能受体激动作用，ec50值为24 pM。它产生一种完全和有效的气道平滑肌松弛作用，与奥替特罗相同。其作用起效时间为3.5 min，作用持续时间大于12 h。这些结果表明(R)-18是长效β2-AR激动剂的潜在候选者。
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 EC50value 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 anin vitroguinea pig trachea model of bronchodilation. These results suggest that(R)-18cis a potential candidate for long-acting β2-AR agonists.