Quinolinones 8hydroxycarbostyril

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Indacaterol, 3 (QAB-149) is currently being developed as a once daily |b2-adrenoceptor agonist for the treatment of COPD and asthma [9]. Indacaterol contains the familiar quinolinone head group that appears in the marketed short-acting p2-adrenoceptor agonist, procaterol, 4. This 8-hydroxycarbostyril moiety is known to have a high affinity for the ^-adrenoceptor and has been postulated to give potential slow offset properties to ligands to drive duration of action [10]. A recently published patent suggests that the maleate salt of indacaterol is highly crystalline, stable, and may be the preferred form of this compound for development and clinical use [11].


Data have recently been disclosed on the pharmacological profile of indacaterol. Using guinea-pig tissue preparations, potency data were generated in guinea-pig atria (EC50 = 21.6 mM) vs. guinea-pig trachea (EC50 = 45 nM), suggesting that the compound has selectivity over the ^-adrenoceptor. Further studies using guinea-pig trachea tissue preparations with electrical field stimulation (EFS)-induced contractions suggest that indacaterol has lower potency than salmeterol (EC50 = 45 vs. 15 nM) but a more rapid onset of action. However, its duration of action was shorter than salmeterol (7 vs.>12h) when tested at 100 nM concentrations [12]. Further profiling of indacaterol in isolated human bronchus using EFS -induced contractions again indicated that the compound was less potent than salmeterol (EC50 = 131 vs. 32 nM). In these experiments, indacaterol was highly efficacious as a bronchodilator and had similar duration of action relative to salmeterol [13].

Indacaterol was profiled using plethysmography in the conscious guinea pig with 5-hydroxytryptamine (5HT)-induced bronchoconstriction. When administered intra-tracheally as a dry powder, indacaterol was more potent than salmeterol (ED50 = 0.22 vs. 1.5 mg/kg) and also showed a superior duration of action at the ED80 dose.

Indacaterol was advanced to human trials using a hydrofluoroalkane-based multi-dose inhaler to deliver the drug in mild-to-moderate asthmatics. It showed long duration of action (>24h) and in some patients a rapid onset of broncho-dilation at higher doses. The 400 mg dose appeared to be statistically superior to placebo at all time points up to 26 h post-dose without generating statistically significant safety concerns [14]. Further data have been released regarding multidose trials where an 800 mg dose was tested against placebo in a 14-day trial in mild to moderate COPD patients. A 24 h duration of action was achieved with no discontinuations due to adverse events. At the 800 mg dose, the pharmacokinetic halflife was shown to be 48 h, with a twofold increase in systemic exposure relative to the 400 mg dose [15]. Phase III studies are due to be completed in 2006 and regulatory submissions are planned for 2007 [16].

An alternative, once daily ^-adrenoceptor agonist that has progressed to clinical trials is carmoterol, 5 (CHF-4226, TA-2005). Structurally, the compound resembles the marketed agent formoterol, while containing the 8-hydroxycarbostyril head group rather than the formamide. Extensive work to understand the preclinical pharmacology of carmoterol and studies using guinea-pig trachea preparations have shown the compound to possess a rapid onset of action and a long duration of action. It has been postulated that the long duration of action is linked to the tight binding of carmoterol to the ^-adrenoceptor [17].



Carmoterol was previously in development and known to have entered Phase I trials; however, no development activities have been reported since 1994 [18]. The compound was then out-licensed for development and studies showed carmoterol to be an effective bronchodilator with a duration of action greater than 24 h [19]. Interest in the compound was renewed and regulatory filings are now anticipated in 2006 [20].

The 8-hydroxycarbostyril ring system has been incorporated in structurally more complex molecules where increased lipophilicity may play a key role in providing duration of action. This is the postulated mechanism used to rationalize the duration of action of salmeterol where it is believed that better membrane partitioning underpins duration, in line with the diffusion micro kinetic theory [21].

Two patents claiming crystalline salt forms of two differing 8-hydroxycarbostyril-containing structures, 6 and 7, have issued [22,23]. The filing of patents around specific salt forms of these compounds, including processes for their preparation and formulation suggests that these are significant compounds in the development pipeline as once daily ^-adrenoceptor agonists.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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