Synthesis and Structure−Activity Relationships of Long-acting β₂ Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

Abstract

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

“…The chemical synthesis of vilanterol is detailed in Procopiou et al (2010). CGP12177 amino]-2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one hydrochloride], formoterol, ICI118551 …”

Pharmacology and Therapeutics of Bronchodilators

“…Vilanterol. Vilanterol, also known as GSK-642444, is the triphenylacetate salt of the 2,6-dichlorobenzyl analog of a series of novel ␤ 2 -AR agonists obtained by the incorporation of an oxygen atom at the homobenzylic position of the right-hand side phenyl ring of (R)-salmeterol (Procopiou et al, 2010). The triphenylacetate salt was found to have suitable properties for inhaled administration.…”

“…Vilanterol has a greater intrinsic efficacy than salmeterol and a greater potency than indacaterol and albuterol. In addition, it has been shown, using human recombinant ␤ 1/2/3 -AR cAMP assays, that it has significantly greater ␤ 2 -AR selectivity than formoterol, indacaterol, and albuterol Procopiou et al, 2010). In isolated electrically stimulated guinea pig tracheal strips, vilanterol [negative logarithm of EC 50 (pEC 50 ) ϭ 8.6] was equipotent with formoterol (pEC 50 ϭ 8.6), more potent than salmeterol (pEC 50 ϭ 6.7) or indacaterol (pEC 50 ϭ 7.0), and was shown to be antagonized in a competitive manner by propranolol .…”

Efficacy and safety of long-acting beta-2-agonists

“…Плотное связывание олодатерола с человечес ким β2 АР и стабилизация тройного комплекса были подтверждены в ходе функциональных эксперимен тов по мониторингу активности аденилатциклазы после отмывания образцов [25]. [26].…”