Discovery of a Highly Selective β2-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent.
Discovery of a Highly Selective β2-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent.
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DOI：
10.1021/acs.jmedchem.1c02006
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发表时间：
2022-04
影响因子：
7.3
通讯作者：
Gang Xing;Dahong Li;A. Woo;Zhengxing Zhi;L. Ji;Rui-juan Xing;Hailiang Lv;B. He;Hui An;Haiyan Zhao;B. Lin;L. Pan;Maosheng Cheng
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文献类型：
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作者：
Gang Xing;Dahong Li;A. Woo;Zhengxing Zhi;L. Ji;Rui-juan Xing;Hailiang Lv;B. He;Hui An;Haiyan Zhao;B. Lin;L. Pan;Maosheng Cheng
资源贫乏国家的哮喘患者无法获得足够的基本哮喘药物，因为大多数哮喘药物以吸入剂的形式提供。另一种方法是制造具有高β2/β1选择性的口服平喘药，这将降低治疗成本。在本研究中，我们设计了一个以2-（4-氨基-3-氯-5-（三氟甲基）苯基）-2-（叔丁基氨基）乙基-1-醇氯化氢（1a）为先导化合物的系列化合物1，旨在扩大具有2-氨基-2-苯乙醇支架的化合物库。这些化合物的构效关系研究表明，与异丙肾上腺素相比，合成的化合物具有显著的β2选择性，并为β2肾上腺素受体激动剂的合理设计提供了新的见解。此外，1a被认为是具有最大药物开发潜力的最佳候选化合物。基于细胞的实验表明，1a对β2-肾上腺素受体的选择性比沙丁胺醇高约10倍。此外，1a具有良好的口服生物利用度和低的急性口服毒性。这些数据显示1a是一种口服平喘药。
Asthma patients in resource-poor countries cannot obtain adequate basic asthma medications because most asthma medications are supplied as inhalants. An alternative approach is to create oral antiasthmatic drugs with high β2/β1-selectivity, which should reduce treatment costs. In this study, we designed a cohort of compounds 1 using 2-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(tert-butylamino)ethan-1-ol hydrogen chloride (1a) as the lead compound with an aim to expand the library of compounds possessing the 2-amino-2-phenylethanol scaffold. Structure-activity relationship studies on these compounds revealed that compounds created showed remarkable β2 selectivity compared to isoproterenol and gave additional insights on the rational design of β2-adrenoceptor agonists. Moreover, 1a was found as the best candidate compound showing the greatest potential for drug development. Cell-based assays showed that 1a was about 10 times more selective than salbutamol toward the β2-adrenoceptor. Moreover, 1a exhibited good oral bioavailability and low acute oral toxicity. These data reveal 1a as an oral antiasthmatic agent.