Discovery and Identification of Novel 5-Hydroxy-4H-benzo[1,4]oxazin-3-one Derivatives as Potent ß2-Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation.

Although ß2-agonists are crucial for treatment of chronic respiratory diseases, optimizing ß2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of ß2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated ß2 adrenoceptors (ß2-ARs). Screening for the ß2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial ß2-agonist in HEK-293 cells containing endogenous ß2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential ß2 agonist candidate for further study.

Discovery of a Highly Selective ß2-Adrenoceptor Agonist with a 2-Amino-2-phenylethanol Scaffold as an Oral Antiasthmatic Agent.

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 ß2/ß1-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 ß2 selectivity compared to isoproterenol and gave additional insights on the rational design of ß2-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 ß2-adrenoceptor. Moreover, 1a exhibited good oral bioavailability and low acute oral toxicity. These data reveal 1a as an oral antiasthmatic agent.

8-Hydroxyquinolin-2(1H)-one analogues as potential ß2-agonists: Design, synthesis and activity study.

ß2-Agonists that bind to plasmalemmal ß2-adrenoceptors causing cAMP accumulation are widely used as bronchodilators in chronic respiratory diseases. Here, we designed and synthesized a group of 8-hydroxyquinolin-2(1H)-one analogues and studied their ß2-agonistic activities with a cellular cAMP assay. Compounds B05 and C08 were identified as potent (EC50 < 20 pM) and selective ß2-agonists among the compounds tested. They behaved as partial ß2-agonists in non-overexpressed HEK293 cells, and possessed rapid smooth muscle relaxant actions and long duration of action in isolated guinea pig tracheal strip preparations. In summary, B05 and C08 are ß2-agonists with potential applicability in chronic respiratory diseases.

Recent progress in the development of ß2 adrenergic receptor agonists: a patent review (2015-2020).

INTRODUCTION: The ß2 adrenergic receptor (ß2AR) is a member of G protein-coupled receptors (GPCRs) that mediate the majority of cellular responses to external stimuli. The agonists can cause smooth muscle relaxation; therefore, many ß2AR agonists have been developed especially for the treatment of pulmonary disorders such as asthma and chronic obstructive pulmonary disease (COPD). Many new natural and synthetic compounds have been discovered and developed as novel ß2AR agonists over the past 5 years. AREAS COVERED: This review offers an update for the development of ß2AR agonists in the patents published from 2015 to 2020, including new natural and synthetic compounds for the treatment of asthma and COPD. In particular, the latest patents about compounds possessing both muscarinic receptor antagonist and ß2 adrenergic receptor agonist activity are reviewed. EXPERT OPINION: ß2AR agonists have been developed extensively for the treatment of asthma and COPD. In the past 5 years, novel agonists from both natural sources and synthetic methods were intensively developed. Compounds possessing both muscarinic receptor antagonist and ß2AR agonist activity represent a new trend in this area because they are possibly able to act together in a synergistic fashion, therefore, relieve the symptoms of patients through two distinct mechanisms.