Discovery of β-arrestin-biased β-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects.

Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β-adrenoceptor agonists.

A novel series of 2-amino-2-phenylethanol derivatives were developed as β-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC = 0.25 nM) in stimulating β-adrenoceptor-mediated cellular cAMP production with a 763.

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

A new series of β-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 EC value of 1.

[Recent advances in study of long β(2)-adrenoceptor agonist].

β2-Adrenoceptor agonists are highly effective bronchodilators and are widely used in the treatment of both chronic obstructive pulmonary disease (COPD) and asthma. In the last 15 years, there has been great interest within the pharmaceutical industry in the discovery of a long β2-adrenoceptor agonist for a mono-therapy or combination therapy. The search for new long-acting β2-adrenoreceptor agonists (LABA’s), for the treatment of asthma and COPD, has become a very active area of drug discovery.