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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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 ₂ Adrenoceptor Agonist with a 24-h Duration of Action

Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom (C.B., S.J.C., M.R.D., R.A.F., J.R.L.-D., C.A.L., L.M., R.J.T.) and Basel, Switzerland (B.C., D.F., J.R.F., A.T.)

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 = 73 ± 1% of the maximal effect of isoprenaline; pEC₅₀ = 8.06 ± 0.02), whereas salmeterol displays only partial efficacy (38 ± 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 ± 4 min) similar to formoterol and salbutamol, and a long duration of action (529 ± 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.

Address correspondence to: Dr. Alexandre Trifilieff, WSJ-386.5.10, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland. E-mail: alexandre.trifilieff{at}novartis.com

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				R. G. Sturton, A. Trifilieff, A. G. Nicholson, and P. J. Barnes Pharmacological Characterization of Indacaterol, a Novel Once Daily Inhaled 2 Adrenoceptor Agonist, on Small Airways in Human and Rat Precision-Cut Lung Slices J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 270 - 275. [Abstract] [Full Text] [PDF]

				K. M. Beeh, E. Derom, F. Kanniess, R. Cameron, M. Higgins, and A. van As Indacaterol, a novel inhaled {beta}2-agonist, provides sustained 24-h bronchodilation in asthma Eur. Respir. J., May 1, 2007; 29(5): 871 - 878. [Abstract] [Full Text] [PDF]

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