Research paperSynthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold
Graphical abstract
Introduction
Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic respiratory diseases that affect millions of people worldwide [1]. Up to 300 million people suffer from asthma globally, and the prevalence of asthma has been increasing by 50% every decade [2]. COPD is a leading cause of morbidity and mortality with a prevalence estimated currently at 9–10% in adults aged 40 years or older [3]. The World Health Organization (WHO) estimated back in 2006 that by 2020 COPD would be the third leading cause of mortality and the fifth leading cause of morbidity in the world [4]. Both of these diseases can be treated with bronchodilators, such as β2-adrenoceptor agonists and muscarinic antagonists. Monotherapy or combination therapy comprising these bronchodilators and inhaled corticosteroids are known to produce relief or reduce the frequency of exacerbation. The more widespread use of these pharmaceutical agents has been one of the major means to lower the burden of chronic respiratory diseases [5].
The β2-adrenorcecptor, a prototypical class A G protein-coupled receptor, is widely distributed in the respiratory tract, especially in airway smooth muscles. Agonists of this receptor exert a bronchodilatory effect through relaxation of airway smooth muscles. Activation of the β2-adrenorcecptor induces an increase of cytoplasmic cAMP concentration and subsequently a decrease of cytoplasmic Ca2+ concentration, which results in a lower muscle tone [6,7]. Bronchodilator β2-agonists may be broadly classified into three generations based on their onset of action and duration of action. The first generation or short-acting β2-agonists with no more than 4–6 h duration of action, such as salbutamol and terbutaline, are used mainly for quick asthma relief [8,9]. The second generation agents are long-acting with a duration of action of about 12 h. Salmeterol, formoterol and other agents in this class are used in persistent asthma and COPD [8]. The ultralong-acting β2-agonists most recently developed such as Novartis' indacaterol [10], Boehringer-Ingelheim's olodaterol [11] and GlaxoSmithKline's vilanterol [12] have duration of action that last for a whole day.
In recent years, at least six candidates of β2-adrenoceptor agonists are under clinical development. These include Pfizer's PF-610355 [1], Theravance's TD-5471 and TD-4306 [13,14], Almirall's abediterol [15], Theravance's milveterol [16] and trantinterol (Fig. 1) developed by our group. Trantinterol is different from the other candidates because it bears a 2-amino-2-phenylethanol scaffold rather than a 2-amino-1-phenylethanol scaffold found in classical β2-agonists. Pharmacological characterization of trantinterol has demonstrated that it is a selective β2-agonist with strong biological activities [17].
In the present study, the head group (8-hydroxy-1H-quinolin-2-one) and the tail group (aminoaryl portion) of indacaterol were combined with the 2-aminoethan-1-ol core of trantinterol to yield the lead compound 5a (Fig. 1) which had an EC50 value of 357.0 nM in an assay for β2-adrenoceptor-mediated cAMP accumulation. To optimize biological activity, a series of 5a analogs with different tail groups were subsequently synthesized and biologically evaluated.
Section snippets
Chemistry
The syntheses of the target compounds 5a-x are illustrated in Scheme 1. The key intermediate 1 was synthesized according to a general procedure [18]. Reduction of 1 with sodium borohydride afforded 2, which was subjected to intramolecular nucleophilic substitution to afford the epoxide 3 in the presence of K2CO3. Intermediates 4a-x were prepared by refluxing 3 with different primary amines in the presence of zinc chloride as catalyst and acetonitrile as solvent. Target compounds 5a-x were
Conclusion
A series of novel β2-adrenoceptor agonists based on the previously identified 2-amino-2-phenylethanol scaffold have been synthesized and evaluated for agonistic activities in β2-adrenoceptor-expressing cells. Highly active compounds were further characterized for receptor subtype selectivity, intrinsic activity and airway smooth muscle relaxant effect. A hit compound (S)-5j was found to have pharmacokinetic properties of an inhaled agent and binding features resembling a β2-agonist. Taken
Chemistry
Unless otherwise noted, all solvents and reagents were obtained from commercial suppliers and were used as received. High resolution ESI-MS was performed on an AB Sciex TripleTOF® 4600 LC/MS/MS system. 1H NMR and 13C NMR spectra were recorded for compounds dissolved in DMSO‑d6 on a Brucker AV400 NMR spectrometer. Chemical shifts (δ) are expressed in parts per million (ppm) relative to the internal control (TMS). 1H NMR spectra are reported in the following order: multiplicity, approximate
Acknowledgments
This work was supported by the National Natural Science Foundation of China (grant number 81673355 to A.Y.-H.W.) and in part by the National Science and Technology Major Project of Ministry of Science and Technology of the People's Republic of China (grant number 2018ZX09739009 to M.C.).
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Authors contributed equally to this work.