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The Identification of Indacaterol as an Ultra-Long-Acting Inhaled Beta-2-Adrenoceptor Agonist

Beattie, David, Beer, David, Bentley, David, Bradley, Michelle, Bruce, Ian, Charlton, Steven, Cuenoud, Bernard, Ernst, Roland, Fairhurst, Robin, Faller, Bernard, Farr, David Colin, Keller, Thomas, Fozard, John R., Fullerton, Joe, Garman, Sheila, Hatto, Julia, Hayden, Claire, He, Handan, Howes, Colin, Janus, Diana, Jiang, Zhengjin, Loeuillet-Ritzler, Frederique, Moser, Heinz, Reilly, John, Steward, Alan, Sykes, David, Tedaldi, Lauren, Trifilieff, Alexandre, Tweed, Morris, Watson, Simon, Wissler, Elke, Wyss, Daniel, Baur, Francois and Charman, Christine (2010) The Identification of Indacaterol as an Ultra-Long-Acting Inhaled Beta-2-Adrenoceptor Agonist. Journal of Medicinal Chemistry, 53. pp. 3675-3684.


Following a lipophilicity-based hypothesis, a series of 2-aminoindan and 8-hydroxyquinolinone derived 2-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultra-long-acting bronchodilators. Determination of their activities at the human 2-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference 2-adrenoceptor agonists. Further assessment with an in vitro super-fused electrically-stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses which could be rationalised by considering the lipophilicity, potency and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung which led to the compound being selected as a development candidate.

Item Type: Article
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Keywords: beta-2 adrenoceptor agonists, asthma, COPD, inhalation, long-acting
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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