Discovery of a Highly Selective β<sub>2</sub>-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent.
Xing G, Li D, Woo AY, Zhi Z, Ji L, Xing R, Lv H, He B, An H, Zhao H, Lin B, Pan L, Cheng M.
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<sub>2</sub>/β<sub>1</sub>-selectivity, which should reduce treatment costs. In this study, we designed a cohort of compounds <b>1</b> using 2-(4-amino-3-chloro-5-(trifluoromethyl)phenyl)-2-(<i>tert</i>-butylamino)ethan-1-ol hydrogen chloride (<b>1a</b>) 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<sub>2</sub> selectivity compared to isoproterenol and gave additional insights on the rational design of β<sub>2</sub>-adrenoceptor agonists. Moreover, <b>1a</b> was found as the best candidate compound showing the greatest potential for drug development. Cell-based assays showed that <b>1a</b> was about 10 times more selective than salbutamol toward the β<sub>2</sub>-adrenoceptor. Moreover, <b>1a</b> exhibited good oral bioavailability and low acute oral toxicity. These data reveal <b>1a</b> as an oral antiasthmatic agent.