In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

Abstract

Here, we describe the preclinical pharmacological profile of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel, chirally pure inhaled ␤ 2 adrenoceptor agonist, in comparison with marketed drugs. Indacaterol is close to a full agonist at the human ␤ 2 adrenoceptor (E max ϭ 73 Ϯ 1% of the maximal effect of isoprenaline; pEC 50 ϭ 8.06 Ϯ 0.02), whereas salmeterol displays only partial efficacy (38 Ϯ 1%). The functional selectivity profile of indacaterol over ␤ 1 human adrenoceptors is similar to that of formoterol, whereas its ␤ 3 adrenoceptor selectivity profile is similar to that of formoterol and salbutamol. In isolated superfused guinea pig trachea, indacaterol has a fast onset of action (30 Ϯ 4 min) similar to formoterol and salbutamol, and a long duration of action (529 Ϯ 99 min) comparable with salmeterol. In the conscious guinea pig, when given intratracheally as a dry powder, indacaterol inhibits 5-hydroxytryptamine-induced bronchoconstriction for at least 24 h, whereas salmeterol, formoterol, and salbutamol have durations of action of 12, 4, and 2 h, respectively. When given via nebulization to anesthetized rhesus monkeys, all of the compounds dose-dependently inhibit methacholine-induced bronchoconstriction, although indacaterol produces the most prolonged bronchoprotective effect and induces the lowest increase in heart rate for a similar degree of antibronchoconstrictor activity. In conclusion, the preclinical profile of indacaterol suggests that this compound has a superior duration of action compatible with once-daily dosing in human, together with a fast onset of action and an improved cardiovascular safety profile over marketed inhaled ␤ 2 adrenoceptor agonists.Agents that act as agonists of the ␤ 2 adrenoceptor are effective in the management of asthma and chronic obstructive pulmonary disease (COPD), primarily through their bronchodilatating properties. These drugs induce bronchodilatation by causing direct relaxation of airway smooth muscle through activation of adenylate cyclase, which in turn increases intracellular cAMP levels.Salbutamol is an inhaled ␤ 2 adrenoceptor agonist that provides rapid bronchodilatation and has been widely used over the past 30 years. However, its major drawback is its short duration of action (4 -6 h), requiring the drug to be administered several times a day. Two longer acting inhaled ␤ 2 adrenoceptor agonists, formoterol and salmeterol, are now available and are used in the management of asthma and COPD (Sutherland, 2004). These two drugs have a bronchodilating effect lasting for 12 h after a single inhalation and are therefore given twice daily. Despite the decrease in dosing frequency with the longer acting inhaled ␤ 2 adrenoceptor agonists, patient compliance is still an issue (Ying et al., 1999). In addition, the recent launch of tiotropium bromide, a once-daily inhaled muscarinic antagonist for the treatment of COPD (Gross, 2004), and the development of once-daily inhaled corticosteroids for the...

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

“…There was a trend toward higher selectivity for abediterol and salmeterol than for formoterol and indacaterol; the comparison between abediterol and salmeterol selectivity ratios was difficult because of the low ␤ 1 efficacy observed for both compounds in guinea pig atria. Our results are consistent with those reported previously, indicating that the ␤ 1 /␤ 2 and ␤ 3 /␤ 2 selectivity ratios of formoterol and indacaterol are inferior to those of salmeterol (Ball et al, 1991;Battram et al, 2006;Bouyssou et al, 2010). In humans, it has been reported that activity at the ␤ 1 -adrenoceptor might be responsible for some of the cardiac side effects associated with ␤-adrenergic agonism (Levine and Leenen, 1989).…”

“…The guinea pig has been widely used to assess the bronchodilator activity of ␤ 2 -agonists (Battram et al, 2006;Bouyssou et al, 2010). In the acetylcholine-induced bronchoconstriction model in anesthetized guinea pigs, abediterol exhibited the highest potency in comparison to reference compounds, in agreement with the potency observed in guinea pig tracheal preparations and human bronchi.…”

Safety, tolerability and efficacy of indacaterol, a novel once-daily β2-agonist, in patients with COPD: A 28-day randomised, placebo controlled clinical trial

“…Preclinical study results suggest that indacaterol has a longer duration of action than either formoterol or salmeterol, with a rapid onset of action, and a potentially greater cardiovascular safety margin compared with formoterol or salmeterol, for a given degree of bronchodilator activity [10]. In clinical studies in patients with asthma, indacaterol has demonstrated effective 24-hour bronchodilation with a rapid onset of action and was shown to be well tolerated with a good overall safety profile [11,12].…”

Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

“…Differences in β1/β2 selectivity are also relevant. For example, in a rhesus monkey model at doses conferring similar (formoterol) or lesser (salmeterol) bronchoprotection versus indacaterol, both formoterol and salmeterol had greater and substantially more prolonged effects upon heart rate than indacaterol (35). These data imply that indacaterol may be dosed closer to its Emax, at least from a cardiovascular safety perspective, than salmeterol or formoterol allow.…”