Discovery of a Highly Selective β2-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent

Journal of Medicinal Chemistry
2022.0

Abstract

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.

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