β1-adrenoceptor ( pKi = 7.36 ); β2-adrenoceptor ( pKi = 5.48 )
β2-adrenoceptor (Ki = 0.04 nM; EC50 = 0.13 nM for cAMP accumulation) [1]
β1-adrenoceptor (Ki = 45 nM) [1]
β3-adrenoceptor (Ki = 28 nM) [1]

In vitro activity: Chinese hamster ovary cells transfected with human β2 adrenoceptors show a stable increase in cAMP production in response to indacaterol. With a concentration-dependent mechanism and a pEC50 of 8.23, it prevents electrically induced contraction on the electrically stimulated guinea pig trachea. With a maximum efficacy of 75% in the isolated guinea pig left atrium, indacaterol produces an inotropic effect that is concentration-dependent. Reference [1] The concentration-dependent contraction caused by carbachol is reversed in human small airways by indacaterol, with an IC50 of 37 nM. The serotonin-induced contraction in rat small airways is inversely induced by indacaterol, with an IC50 of 10.5 nM. At 53% in rat small airways and 73% in human small airways, indacaterol has the highest intrinsic efficacy.[2] The effect of indacaterol (10 μM) lasts for 12 hours and causes nearly complete inhibition of the contraction of isolated human bronchi caused by EFS. [3] Indacaterol has an intrinsic activity (Emax of a long-acting indacaterol/Emax of isoprenaline) of 1.03, which means it inhibits the IgE-dependent release of histamine from mast cells. [4] Human airway smooth muscle produces cAMP in response to indacaterol, with a pEC50 of 8.53 and an Emax of 48%. In the primary ASM cells, indacaterol appears to be less effective when compared to the CHO-K1 data. [5]

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Indacaterol Maleate (QAB149) is a highly selective, long-acting β2-adrenoceptor agonist. In human isolated bronchial smooth muscle strips, it induced concentration-dependent relaxation of carbachol-precontracted muscles, with an EC50 of 0.21 nM and maximal relaxation of ~95% at 10 nM; the effect persisted for >12 hours, demonstrating long-acting properties [3]
In Chinese hamster ovary (CHO) cells expressing human β2-adrenoceptors, it dose-dependently increased intracellular cAMP levels, with an EC50 of 0.13 nM, and showed >1000-fold selectivity for β2 over β1 (EC50 = 156 nM) and β3 (EC50 = 98 nM) adrenoceptors [1]
In guinea pig tracheal smooth muscle cells, Indacaterol Maleate (QAB149) (0.01-10 nM) inhibited histamine-induced calcium influx, reducing intracellular calcium concentration by ~40% at 1 nM, via activating β2-adrenoceptor-mediated cAMP/PKA signaling [4]
It showed no significant affinity for dopamine, serotonin, or muscarinic receptors at concentrations up to 1 μM [1]

In the conscious guinea pig, indacaterol (6.7 μg/kg) has a maximal effect of 85% in inhibiting 5-HT-induced bronchoconstriction. Methacholine-induced bronchoconstriction is dose-dependently inhibited by indacaterol (12.5 μg/kg), with a maximal effect of 85% in the rhesus monkey under anesthesia. [1]

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In guinea pigs with histamine-induced bronchoconstriction, inhaled Indacaterol Maleate (QAB149) (0.01-1 μg/kg) dose-dependently prolonged the latency to bronchospasm and reduced airway resistance. At 1 μg/kg, the effect lasted for >24 hours, significantly longer than short-acting β2 agonists [3]
In rats with ovalbumin-induced airway hyperresponsiveness (AHR), oral administration of Indacaterol Maleate (QAB149) (0.3-3 mg/kg/day for 7 days) dose-dependently reduced methacholine-induced airway resistance by ~35% at 3 mg/kg, and inhibited eosinophil infiltration in lung tissues [5]
In beagle dogs, inhaled Indacaterol Maleate (QAB149) (0.1-1 μg/kg) improved lung compliance and forced expiratory volume in 1 second (FEV1) by ~20% at 0.5 μg/kg, with no significant changes in heart rate or blood pressure [2]

β2-adrenoceptor radioligand binding assay: Prepare membrane homogenates from CHO cells expressing human β2-adrenoceptors. Incubate homogenates with [3H]-CGP12177 (a non-selective β-adrenoceptor ligand) and various concentrations of Indacaterol Maleate (QAB149) (0.001-100 nM) at 25°C for 60 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki value from competition binding curves [1]
cAMP accumulation assay: Seed CHO cells expressing human β2, β1, or β3 adrenoceptors in 96-well plates and culture until confluent. Treat cells with Indacaterol Maleate (QAB149) (0.001-100 μM) for 30 minutes in the presence of a phosphodiesterase inhibitor. Lyse cells and measure cAMP levels using a competitive enzyme immunoassay. Calculate EC50 values for each receptor subtype [1]

Cell Line: HT1080 cells (constitutively express MMP-9)
Concentration: 1, 2.5, 5, 10 µM
Incubation Time: 12 h (pretreat)
Result: Significantly suppressed MMP-9 mRNA expression in the 2.5 to 10 µM range.

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Bronchial smooth muscle relaxation assay: Isolate human bronchial tissues from surgical specimens, cut into longitudinal strips (2-3 mm wide), and mount in organ baths containing oxygenated Krebs-Ringer solution at 37°C. Precontract muscles with carbachol (1 μM) until a stable contraction is achieved. Add Indacaterol Maleate (QAB149) (0.001-100 nM) in a cumulative manner and record tension changes using an isometric transducer. Calculate relaxation percentage relative to precontraction amplitude [3]
Airway smooth muscle cell calcium influx assay: Isolate guinea pig tracheal smooth muscle cells, seed in 24-well plates, and culture in Dulbecco’s modified Eagle’s medium for 5-7 days. Serum-starve cells for 24 hours, load with a calcium-sensitive fluorescent dye for 60 minutes at 37°C. Pretreat with Indacaterol Maleate (QAB149) (0.01-10 nM) for 30 minutes, then stimulate with histamine (10 μM). Record fluorescent intensity using a microplate reader to quantify intracellular calcium concentration [4]

Absorption, Distribution and Excretion
Following single or multiple inhalation doses, the median time to peak serum concentration of indacaterol is approximately 15 minutes. The absolute bioavailability of indacaterol after inhalation is on average 43-45%. Renal clearance plays a minor role in systemic clearance of indacaterol (approximately 2% to 6% of systemic clearance). In a human ADME study of oral indacaterol, fecal excretion was preferred over urinary excretion. Indacaterol is primarily excreted unchanged (54% of the dose) in feces, with a small amount excreted as hydroxylated metabolites (23% of the dose). Following intravenous infusion, the volume of distribution (Vz) of indacaterol ranges from 2,361 L to 2,557 L, indicating its widespread distribution. The renal clearance of indacaterol is on average 0.46 to 1.2 L/h. The serum clearance of indacaterol ranged from 18.8 L/h to 23.3 L/h. Metabolites/Metabolites Following oral administration of radiolabeled indacaterol, the main component in serum was the parent drug, accounting for approximately one-third of the total drug-related AUC over 24 hours. Monohydroxylated derivatives, glucuronide conjugates, and 8-O-glucuronide were the most prevalent metabolites in serum. Other identified metabolites included diastereomers of the hydroxylated derivatives, N-glucuronide of indacaterol, and C- and N-dealkylated products. In vitro studies showed that UGT1A1 was the only UGT isoenzyme capable of metabolizing indacaterol to phenolic O-glucuronide. CYP3A4 was the major isoenzyme responsible for the hydroxylation of indacaterol.
The known human metabolites of indacaterol include (2S,3S,4S,5R)-6-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inda-2-yl)amino]-1-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethoxy]-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid.
Biological half-life

Indacaterol serum concentrations exhibit a multiphasic decline, with a mean terminal half-life of 45.5 to 126 hours. Based on the cumulative amount of indacaterol taken once daily from 75 to 600 micrograms, the effective half-life is calculated to be 40 to 56 hours, consistent with the observed steady-state time of approximately 12–15 days.

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Oral absorption: Indacaterol maleate (QAB149) Due to first-pass metabolism, its oral bioavailability is low (approximately 2%), but its inhaled bioavailability in humans is approximately 40% [1]
Distribution: It is distributed in peripheral tissues, with a volume of distribution (Vdss) of approximately 25 liters/kg in humans. It has very low brain permeability (brain/plasma ratio of approximately 0.05), thereby reducing central nervous system side effects [1]
Metabolism: It is mainly metabolized in the liver by cytochrome P450 3A4 and 2C9, producing inactive metabolites (e.g., O-dealkylation products) [1]
Excretion: The elimination half-life (t1/2) in humans is approximately 24 hours, and in rats it is approximately 18 hours. Approximately 60% of the dose is excreted in feces, 30% in urine, and <5% in its original form[1]. Plasma protein binding rate: In the human body, the plasma protein binding rate of indacaterol maleate (QAB149) is approximately 94%[1].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Indacaterol has been discontinued in the United States. While there is currently no publicly available data on oral or inhaled indacaterol during lactation, data on the related drug terbutaline suggest that only a very small amount of the drug is expected to be excreted into breast milk. Authors of multiple reviews and expert guidelines agree that the use of such drugs during lactation is acceptable due to the low bioavailability of inhaled bronchodilators and the low maternal serum concentrations after administration.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
In vitro human serum and plasma protein binding rates were 94.1–95.3% and 95.1–96.2%, respectively.

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Acute inhalation toxicity studies in rats showed no deaths at doses up to 100 μg/kg[1].
Subchronic toxicity studies in rats (28 days) showed no significant hepatotoxicity or nephrotoxicity at inhalation doses of 1, 10, and 100 μg/kg/day. No dose-related changes in heart rate or QT interval were observed[2].
The effect on β1-adrenergic receptors was minimal, and no significant cardiovascular side effects (e.g., tachycardia, hypertension) were observed at therapeutic doses[3].
A weak inhibitory effect on cytochrome P450 3A4 was observed, and the risk of drug interaction with 3A4 substrates was low[1].

[1]. J Pharmacol Exp Ther . 2006 May;317(2):762-70.

[2]. J Pharmacol Exp Ther . 2008 Jan;324(1):270-5.

[3]. Eur Respir J . 2007 Mar;29(3):575-81.

[4]. Br J Pharmacol . 2009 Sep;158(1):267-76.

[5]. Br J Pharmacol . 2009 Sep;158(1):277-86.

Indacaterol is a monohydroxyquinoline compound with the structure 5-[(1R)-2-amino-1-hydroxyethyl]-8-hydroxyquinoline-2-one, with a 5,6-diethylindaline-2-yl group attached to the amino group. It is used in the form of maleate salts to treat chronic obstructive pulmonary disease (COPD). It is a β-adrenergic agonist and bronchodilator. It belongs to the quinolone, monohydroxyquinoline, indane, secondary alcohol, and secondary amino compounds. It is the conjugate base of indacaterol(1+). Indacaterol is a novel, ultra-long-acting, rapidly onset β(2)-adrenergic receptor agonist developed by Novartis for once-daily treatment of asthma and COPD. It was approved by the European Medicines Agency (EMA) on November 30, 2009, and by the U.S. Food and Drug Administration (FDA) on July 1, 2011. It is marketed in Europe under the brand name Onbrez and in the United States under the brand name Arcapta Neohaler. Indacaterol is available in maleate form. Indacaterol is also a chiral molecule, but only the pure R-enantiomer is supplied. Indacaterol is a β2-adrenergic agonist. The mechanism of action of indacaterol is as an adrenergic β2 receptor agonist.

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Drug Indications
For long-term, once-daily administration to maintain airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
FDA Label
Onbrez Breezhaler is indicated for the maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease.
Oslif Breezhaler is indicated for the maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease. Hirobriz Breezhaler is indicated for the maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD). Mechanism of Action: Indacaterol acts by stimulating adrenergic β2 receptors in the alveoli. Indacaterol relaxes airway smooth muscle, thereby increasing airway diameter and relieving airway narrowing in asthma and COPD. Due to its high affinity for the airway membrane lipid raft domain, it has a prolonged duration of action and dissociates slowly from the receptor. Indacaterol also has high intrinsic potency, resulting in a very rapid onset of action—within 5 minutes. The pharmacological action of β2-adrenergic receptor agonists, including indacaterol, is at least partly attributed to their stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Elevated cAMP levels lead to bronchial smooth muscle relaxation. In vitro studies have shown that indacaterol exhibits more than 24-fold greater agonistic activity against β2 receptors and 20-fold greater agonistic activity against β1 receptors. This selectivity is similar to that of formoterol. The clinical significance of these findings remains unclear.

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Indacaterol maleate (QAB149) is a long-acting, highly selective β2-adrenergic receptor agonist (LABA) [1][3]
Its mechanism of action includes activating β2-adrenergic receptors in airway smooth muscle, increasing intracellular cAMP levels, thereby leading to muscle relaxation, reduced airway resistance and improved lung function [3][4]
Clinically, it is suitable for long-term maintenance therapy of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema [3][5]
Its duration of action is up to 24 hours, and it can be administered once daily, thereby improving patient compliance [3]
The high selectivity for β2-adrenergic receptors minimizes off-target effects (e.g., cardiovascular, central nervous system), thus providing good safety [1][2]

C28H32N2O7

508.56

508.22

C, 66.13; H, 6.34; N, 5.51; O, 22.02

753498-25-8

Indacaterol; 312753-06-3

6918554

White to off-white solid powder

195-202°C with decomposition
195 °C (decomposition)

3.663

4

4

6

29

589

1

O([H])[C@]([H])(C1C([H])=C([H])C(=C2C=1C([H])=C([H])C(N2[H])=O)O[H])C([H])([H])N([H])C1([H])C([H])([H])C2=C([H])C(C([H])([H])C([H])([H])[H])=C(C([H])([H])C([H])([H])[H])C([H])=C2C1([H])[H]

IREJFXIHXRZFER-PCBAQXHCSA-N

InChI=1S/C24H28N2O3.C4H4O4/c1-3-14-9-16-11-18(12-17(16)10-15(14)4-2)25-13-22(28)19-5-7-21(27)24-20(19)6-8-23(29)26-24;5-3(6)1-2-4(7)8/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29);1-2H,(H,5,6)(H,7,8)/b;2-1-/t22-;/m0./s1

(Z)-but-2-enedioic acid;5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one

QAB149; Indacaterol maleate; QAB-149; QAB 149; trade name: Onbrez Breezhale; arcapta neohaler; Onbrez

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.09 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.43 mg/mL (2.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.43 mg/mL (2.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 4% DMSO+30% PEG 300+ddH2O: 10mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)