Synthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold

• Published in: European journal of medicinal chemistry Vol. 152; pp. 424 - 435
• Main Authors: Ge, Xinyue, Woo, Anthony Yiu-Ho, Xing, Gang, Lu, Yali, Mo, Yongmei, Zhao, Ying, Lan, Yi, Li, Jinyan, Yan, Haining, Pan, Li, Zhang, Yuyang, Lin, Bin, Cheng, Maosheng
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 25.05.2018
• Subjects: Bronchodilators; Indacaterol; Trantinterol; β2-Adrenoceptor agonists; β2-Adrenoceptor agonists; Bronchodilators; Indacaterol; Trantinterol
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.041

A new series of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating β2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2 than for the β1 subtype. The putative binding mode of (S)-5j revealed by molecular docking of the β2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of β2-adrenoceptor agonists. [Display omitted] •Synthesis of 26 new β2-agonists with a non-classical 2-amino-2-phenylethanol core.•(S)-5j is the most potent and selective in the series for β2-adrenoceptor activation.•(S)-5j is ≈1000 fold more selective than isoprenaline for β2- vs β1-adrenoceptors.•(S)-5j relaxes airway smooth muscles and permeates human colon cells poorly in vitro.•(S)-5j possesses the characteristics of an inhaled bronchodilator drug.