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

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 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.

Discovery and Identification of Novel 5-Hydroxy-4H-benzo[1,4]oxazin-3-one Derivatives as Potent β2-Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation

“…Inspired by the β 2 -agonistic activity, β 2 /β 1 -selectivity, and smooth muscle relaxant effects of the compounds, their capacity to induce maximal cAMP accumulation was assessed in HEK-293 cells endogenously expressing human β 2 -ARs. The results were quantified in terms of intrinsic activity (IA, %), ,− representing the maximal response of the test compound relative to the maximum effect produced by isoprenaline that exhibits high intrinsic efficacy. Notably, isoprenaline, by definition, exhibits an intrinsic activity of 100%.…”

Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines

“…More importantly, asymmetric transfer hydrogenation has a tremendous advantage over pressurized hydrogenation reactions due to nonaccessibility of the pressurized equipment. Chiral 1,2-amino alcohols are prevalent structural motifs in many pharmaceutical molecules, such as epinephrine, whose indication is for emergency treatment of Type I allergic reactions, including anaphylaxis, and for increasing mean arterial blood pressure in patients with hypotension associated with cardiac arrest or septic shock . The other drugs include Norepinephrine for the treatment of patients in vasodilatory shock states such as septic shock and neurogenic shock .…”

Interaction of twenty-two carbazole derivatives with M1-muscarinic receptor using a theoretical model

“…Other data displayed the preparation of a 2-Amino-2-phenylethanol analog as a selective β2-adrenoceptor agonist to treat asthma in vitro (Xing et al, 2022). Other studies displayed the preparation of an anti-asthmatic drug (fevipiprant) through of DP2-receptor inhibition (Sandham et al, 2017).…”