Abstract
β2-Adrenoceptor agonists have been used as bronchodilators for the treatment of asthma and COPD for over a century. Throughout this period, β2-adrenoceptor agonists have continued to evolve to best meet the needs of the patient, with improvements having been made to the selectivity, route of administration and duration of effect. As the next step in the progression of this class of compound, ultra-long-acting inhaled β2-adrenoceptor agonists, suitable for once-daily dosing, have been targeted to provide a new gold standard in patient compliance. Indacaterol is the first of these agents to be approved for the treatment of COPD, having been designed by a rationale approach to deliver the optimal ultra-long-acting inhaled β2-adrenoceptor agonist profile. Indacaterol was designed following a lipophilicity-based hypothesis to maximise the retention of the compound in the airways, so as to be able to deliver the primary goal of 24 h bronchodilation following a single inhaled dose. Further evaluation then ensured the long duration of effect could be combined with the best overall profile with respect to potency, selectivity, onset of action and side-effect profile. Following the synthesis of a series of close analogues, in which all three regions of the pharmacophore were modified, indacaterol could be confirmed as the optimal compound from the series. Studies to better understand the mechanisms by which indacaterol achieves the observed pharmacological profile are discussed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Waldeck B (2002) β-Adrenoceptor agonists and asthma—100 years of development. Eur J Pharmacol 225:1–12
Kemp JP, Meltzer EO (1990) β2-Adrenergic agonists—oral or aerosol for the treatment of asthma? J Asthma 27:149–157
Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D (2010) The identification of indacaterol as an ultralong-acting inhaled β2-adrenoceptor agonist. J Med Chem 53:3675–3684
Lotvall J (2001) Pharmacological similarities and differences between beta2-agonists. Respir Med 95:S7–S11
Frois C, Wu EQ, Ray S, Colice GL (2009) Inhaled corticosteroids or long-acting β-agonists alone or in fixed-dose combinations in asthma treatment: a systematic review of fluticasone/budesonide and formoterol/salmeterol. Clin Ther 31:2779–2803
Jacobsen JR (2011) Third-generation long-acting β2-adrenoceptor agonists: medicinal chemistry strategies employed in the identification of once-daily inhaled β2-adrenoceptor agonists. Future Med Chem 3:1607–1622
Matera MG, Cazzola M (2007) Ultra-long-acting β2-adrenoceptor agonists an emerging therapeutic option for asthma and COPD. Drugs 67:503–515
Cazzola M, Segreti A, Matera MG (2010) Novel bronchodilators in asthma. Curr Opin Pulm Med 16:6–12
Cazzola M, Matera MG (2008) Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol 155:291–299
Kikkawa H, Kanno K, Ikezawa K (1994) TA-2005, a novel long-acting, and selective beta-2 adrenoceptor agonist: characterisation of its in vivo bronchodilating action in guinea pigs and cats in comparison with other beta-2 agonists. Biol Pharm Bull 17:1047–1052
Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A (2010) Pharmacological characterisation of olodaterol, a novel inhaled β2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther 334:53–62
Jacobsen JR, Choi SK, Comds J, Fournier EJL, Klein U, Pfeiffer JW, Thomas GR, Yu C, Moran EJ (2012) A multivalent approach to the discovery of long-acting β2-adrenoceptor agonists for the treatment of asthma and COPD. Bioorg Med Chem Lett 22:1213–1218
Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Box PC, Butchers PR, Coe DM, Conroy R, Emmons A, Ford AJ, Holmes DS, Horsley H, Kerr F, Li-Kwai-Cheung A-M, Looker BE, Mann IS, McLay IM, Morrison VS, Mutch PJ, Smith CE, Tomlin P (2010) Synthesis and structure-activity relationships of long-acting β2-adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. J Med Chem 53:4522–4530
Puig Duran C, Crespo Crespo MI, Castro Palomino Laria JC, Gual Roig S, Navarro Romero E (2006) Preparation of 4-(2-amino-1-hydroxyethyl)phenol derivatives as agonists of the β2-adrenergic receptor. WO 06/122788
Glossop PA, Lane CAL, Price DA, Bunnage ME, Lewthwaite RA, James K, Brown AD, Yeadon M, Perros-Huguet C, Trevethick MA, Clarke NP, Webster R, Jones RM, Burrows JL, Feeder N, Taylor SCJ, Spence FJ (2010) Inhalation by design: novel ultra-long-acting β2-adrenoceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilise a sulphonamide agonist head group. J Med Chem 53:6640–6652
Norman P (2009) Which of three structures is AZD-3199? WO-2008104790, WO-2008096112 and WO-2009096119. Expert Opin Ther Pat 19:1157–1183
Patil PN, Li C, Kumari V, Hieble JP (2008) Analysis of efficacy of chiral adrenergic agonists. Chirality 20:529–543
King P (2008) Role of arformoterol in the management of COPD. Int J Chron Obstruct Pulmon Dis 3:385–391
Cote C, Pearle JL, Sharafkhaneh A, Spangenthal S (2009) Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: a multicenter, randomized trial. Pulm Pharmacol Ther 22:44–49
White MV, Sander N (1999) Asthma from the perspective of the patient. J Allergy Clin Immunol 104:47–52
Anderson GP, Lindén A, Rabe KF (1994) Why are long-acting β2-adrenoceptor agonists long-acting? Eur Respir J 7:569–578
Coleman RA, Johnson M, Nials AT, Vardey CJ (1996) Exosites: their current status and their relevance to the duration of action of long-acting β2-adrenoceptor agonists. Trends Pharmacol Sci 17:324–330
Deyrup MD, Nowicki ST, Richards NGJ, Otero DH, Harrsison JK, Baker SP (1999) Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor. Naunyn Schmiedebergs Arch Pharmacol 359:168–177
Voss H-P, Donnell D, Bast A (1992) Atypical molecular pharmacology of a new long-acting β2-adrenoceptor agonist, TA 2005. Eur J Pharmacol 227:403–409
Rosethorne EM, Turner RJ, Fairhurst RA, Charlton SJ (2010) Efficacy is a contributing factor to the clinical onset of bronchodilation of inhaled beta(2)-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmacol 382:255–263
Patton JS, Byron PR (2007) Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov 6:67–73
Alikhani V, Beer D, Bentley D, Bruce I, Cuenoud BM, Fairhurst RA, Gedeck P, Haberthuer S, Hayden C, Janus D, Jordan L, Smithies K, Wissler E (2004) Long-chain formoterol analogues: an investigation into the effect of increasing amino-substituent chain length on the β2-adrenoceptor activity. Bioorg Med Chem Lett 14:4705–4710
Naline E, Trifilieff A, Fairhust RA, Advenier C, Molimard M (2007) Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi. Eur Respir J 29:575–581
Yoshizaki S, Tanimura K, Tamada S, Yabuuchi Y, Nakagawa K (1976) Sympathomimetic amines having a carbostyril nucleus. J Med Chem 19:1138–1142
Voss HP (1994) Long-acting β2-adrenoceptor agonists in asthma: molecular pharmacological aspects. Ph.D., thesis, VrijeUniversiteit, Amsterdam
Erös D, Kövesdi I, Örfi L, Takács-Novák K, Acsády G, Kéri G (2002) Reliability of logP predictions based on calculated molecular descriptors: a critical review. Curr Med Chem 9:1819–1829
Battram C, Charlton SJ, Cuenoud B, Dowling MR, Fairhurst RA, Farr D, Fozard JR, Leighton-Davies JR, Lewis CA, McEvoy L, Turner RJ, Trifilieff A (2006) In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quino lin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action. J Pharmacol Exp Ther 317:762–770
Beattie D, Beer D, Bradley ME, Bruce I, Charlton SJ, Cuenoud BM, Fairhurst RA, Farr D, Fozard JR, Janus D, Rosethorne EM, Sandham DA, Sykes DA, Trifilieff A, Turner KL, Wissler E (2012) An investigation into the structure activity relationships associated with the systematic modification of the β2-adrenoceptor agonist indacaterol. Bioorg Med Chem Lett 22:6280–6285
Cuenoud B, Bruce I, Fairhurst RA, Beattie D (2000) Preparation of indanyl-substituted quinolinone derivatives as β2-adrenoceptor agonists. WO 00/075114
Kaiser C (1980) Chapter 13: Drugs affecting the respiratory system. ACS symposium series, 118:251–283
Pilcer G, Amighi K (2010) Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm 392:1–19
Beattie D, Bradley M, Brearley A, Charlton SJ, Cuenoud BM, Fairhurst RA, Gedeck P, Gosling M, Janus D, Jones D, Lewis C, McCarthy C, Oakman H, Stringer R, Taylor RJ, Tuffnell A (2010) A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of β2-adrenoceptor agonists as inhaled long-acting bronchodilators. Bioorg Med Chem Lett 20:5302–5307
Austin RP, Barton P, Bonnert RV, Brown RC, Cage PA, Cheshire DR, Davis AM, Dougall IG, Ince F, Pairaudeau G, Young A (2003) QSAR and the rational design of long-acting dual D2-receptor/β2-adrenoceptor agonists. J Med Chem 46:3210–3220
Valko K, Du CM, Bevan CD, Reynolds DP, Abraham MH (2000) Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures. J Pharm Sci 89:1085–1096
Lombardi D, Cuenoud B, Kramer SD (2009) Lipid membrane interaction of indacaterol and salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 38:533–547
Halayko AJ, Tran T, Gosens R (2008) Phenotype and functional plasticity of airway smooth muscle: role of caveolae and caveolins. Proc Am Thorac Soc 5:80–88
Vauquelin G, Charlton SJ (2010) Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action. Br J Pharmacol 161:488–508
Sykes DA, Charlton SJ (2012) Slow receptor dissociation is not a key factor in the duration of action of inhaled long acting β2-adrenoceptor agonists. Br J Pharmacol 165:2672–2683
Guhan AR, Cooper S, Oborne J, Lewis S, Bennett J, Tattersfield AE (2000) Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects. Thorax 55:650–656
Rabe KF, Lindén A (1997) Mechanisms of duration of action of inhaled long-acting β2-adrenoceptor agonists. In: Pauwels R, O’Byrne PM (eds) Lung biology in health and disease, vol 106, β2-agonists in asthma treatment. Dekker, New York, NY, pp 131–160
Dhillon S, Wagstaff AJ (2008) Ciclesonide nasal spray: in allergic rhinitis. Drugs 68:875–883
Zitt MJ (2005) Properties of the ideal corticosteroid therapy. Allergy Asthma Proc 26:173–182
Rosenborg J, Larsson P, Tegnér K, Hallström G (1999) Mass balance and metabolism of {3H}formoterol in healthy men after combined IV and oral administration-mimicking inhalation. Drug Metab Dispos 27:1104–1116
Reilly J, Etheridge D, Everatt B, Jiang Z, Aldcroft C, Wright P, Clemens I, Cox B, Press NJ, Watson S, Porter D, Springer C, Fairhurst RA (2011) Studies in drug albumin binding using HSA and RSA affinity methods. J Liq Chromatogr Relat Technol 34:317–327
Yata N, Toyoda T, Murakami T, Nishiura A, Higashi Y (1990) Phosphatidylserine as a determinant for the tissue distribution of weakly basic drugs in rats. Pharm Res 7:1019–1025
Nishiura A, Murakami T, Higashi Y, Yata N (1988) Role of phosphatidylserine in the cellular and subcellular lung distribution of quinidine in rats. Pharm Res 5:209–213
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Basel
About this chapter
Cite this chapter
Fairhurst, R.A., Charlton, S.J., Trifilieff, A. (2014). The Design of the Indacaterol Molecule. In: Trifilieff, A. (eds) Indacaterol. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0709-8_3
Download citation
DOI: https://doi.org/10.1007/978-3-0348-0709-8_3
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0348-0708-1
Online ISBN: 978-3-0348-0709-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)