β1-adrenoceptor ( pKi = 7.36 ); β2-adrenoceptor ( pKi = 5.48 )

Indacaterol (1, 2.5, 5, 10 μM; 12 h) inhibits TNF-α-induced MMP-9 and expression activity in human fibrosarcoma HT1080 cells [1]. Indacaterol (10 μM; 6 h) reduces the expression activity of MMP-9 [1]. Indacaterol (1, 2.5, 5, 10 μM; 2.5 h) inhibits TNF-α-activated IKK/NF-кB expression and activity in HT1080 cells and inhibits TNF-α-activated human fibrosarcoma cells most effectively and migrates [ 1]. Cell Viability Assay[1] Cell Line: HT1080 cells (constitutivelyexpress MMP-9) Concentration: 1, 2.5, 5, 10 µM Incubation Time: 12 h (pretreat) Results: Significantly inhibited MMP-9 mRNA. Expression range is 2.5 to 10 µM. Cell migration assay[1] Cell line: HT1080 cells (constitutively expressing MMP-9) Concentration: 10 µM Incubation time: 6 hours (2 hours pretreatment followed by 4 hours incubation with TNF-α) Results: Significant reduction of fibrosarcoma and inhibited HT1080 cell migration in the wound healing area. Western Blot Analysis[1] Cell line: HT1080 Cell concentration: 1, 2.5, 5, 10 µM Incubation time: 2.5 hours (pretreatment for 2 hours, then incubated with TNF-α for 0.5 hours) Results: Inhibition of TNF-α induction of IκBα and Phosphorylation of IKKα/β, the upstream activator of NF-κB. Inhibits TNF-α-induced NF-κB nuclear translocation at 5 and 10 µM. Inhibits TNF-α-induced MMP-9 enzyme activity and reduces MMP-9 protein levels in a dose-dependent manner in the range of 2.5 to 10 µM.

Indacaterol (0.3 mg/kg; MI; once daily for 15 weeks) exhibits normalizing and MI-restoring activity in a myocardial infarction (MI) cardiovascular model of heart failure (HF) [2]. Male Wistar rats (225-250 g; heart failure (HF) myocardial infarction (MI) rat model) [2]. Dosage: 0.3 mg/kg Administration: In drinking water of animals; once daily for 15 weeks Results: Mean arterial blood pressure and heart rate were significantly reduced. Both systolic and diastolic blood pressure LVID increase in heart failure and reverse the decrease in ejection fraction (%) values. Significantly reduced infarct size and catecholamine values to basal levels. β1 mRNA expression and cardiac cAMP levels were significantly increased in association with HF.

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.

Male Wistar rats (225-250 g; myocardial infarction (MI) rat model of heart failure (HF))
0.3 mg/kg
In animal drinking water; sinle daily for 15 weeks

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 the 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.

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Biological half-life
Indacaterol serum concentrations exhibit a multiphasic decline, with a mean terminal half-life of 45.5 to 126 hours. Based on once-daily administration of doses ranging from 75 to 600 micrograms of indacaterol and calculation of cumulative amounts, an effective half-life of 40 to 56 hours was derived, consistent with the observed time to reach steady state of approximately 12–15 days.

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
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.

[1]. Indacaterol inhibits tumor cell invasiveness and MMP-9 expression by suppressing IKK/NF-κB activation. Mol Cells. 2014 Aug;37(8):585-91.

[2]. Effects of the new ultra-long-acting β2-AR agonist indacaterol in chronic treatment alone or in combination with the β1-AR blocker metoprolol on cardiac remodelling. 2015.

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 smooth muscle of the airways. This leads to muscle relaxation, thereby increasing the airway diameter, whereas airway constriction is common in patients with asthma and COPD. Due to its high affinity for the lipid raft domain of the airway membrane, it has a prolonged duration of action and can slowly dissociate 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.

C24H28N2O3

392.49100

392.21

C, 73.44; H, 7.19; N, 7.14; O, 12.23

312753-06-3

Indacaterol maleate; 753498-25-8; Indacaterol-d3; 2699828-16-3

6918554

White to yellow solid powder

1.27

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

3.539

4

4

6

29

589

1

OC1=CC=C([C@@H](O)CNC2CC(C=C(CC)C(CC)=C3)=C3C2)C4=C1NC(C=C4)=O

QZZUEBNBZAPZLX-QFIPXVFZSA-N

InChI=1S/C24H28N2O3/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/h5-10,18,22,25,27-28H,3-4,11-13H2,1-2H3,(H,26,29)/t22-/m0/s1

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

QAB-149; QAB149; QAB149; QAB149-AFA; QAB-149-AFA; Arcapta; Onbrez

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 52~62.5 mg/mL (132.5~159.2 mM)
Ethanol: ~20 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.30 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 20.8 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 2: ≥ 2.08 mg/mL (5.30 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 3: ≥ 2.08 mg/mL (5.30 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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