Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2022 Apr 14;65(7):5514-5527. doi: 10.1021/acs.jmedchem.1c02006. Epub 2022 Apr 1.
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 β/β-selectivity, which should reduce treatment costs. In this study, we designed a cohort of compounds using 2-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(-butylamino)ethan-1-ol hydrogen chloride () 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 β selectivity compared to isoproterenol and gave additional insights on the rational design of β-adrenoceptor agonists. Moreover, was found as the best candidate compound showing the greatest potential for drug development. Cell-based assays showed that was about 10 times more selective than salbutamol toward the β-adrenoceptor. Moreover, exhibited good oral bioavailability and low acute oral toxicity. These data reveal as an oral antiasthmatic agent.
哮喘患者在资源匮乏的国家无法获得足够的基本哮喘药物，因为大多数哮喘药物都是以吸入剂的形式提供的。另一种方法是制造具有高β/β-选择性的口服抗哮喘药物，这应该会降低治疗成本。在这项研究中，我们设计了一组化合物，以 2-(4-氨基-3-氯-5-(三氟甲基)苯基)-2-(-丁基氨基)乙醇盐酸盐（）作为先导化合物，目的是扩展具有 2-氨基-2-苯乙醇骨架的化合物库。对这些化合物的构效关系研究表明，与异丙肾上腺素相比，所合成的化合物表现出显著的β选择性，并为β-肾上腺素受体激动剂的合理设计提供了更多的见解。此外，还发现是表现出最大药物开发潜力的最佳候选化合物。基于细胞的测定表明，与沙丁胺醇相比，对β-肾上腺素受体的选择性约高 10 倍。此外，还表现出良好的口服生物利用度和低急性口服毒性。这些数据表明是一种口服抗哮喘药物。
