Identification

Name
Indacaterol
Accession Number
DB05039
Type
Small Molecule
Groups
Approved
Description

Indacaterol is a novel, ultra-long-acting, rapid onset β(2)-adrenoceptor agonist developed for Novartis for the once-daily management of asthma and chronic obstructive pulmonary disease. It was approved by the European Medicines Agency (EMA) under the trade name Onbrez on November 30, 2009, and by the United States Food and Drug Administration (FDA), under the trade name Arcapta Neohaler, on July 1, 2011. Indacaterol is provided as its maleate salt form. Indacaterol is also a chiral molecule but only the pure R-enantiomer is dispensed.

Structure
Thumb
Synonyms
  • Indacaterol
External IDs
QAB 149 / QAB-149 / QAB149 / QVA-149 COMPONENT INDACATEROL
Product Ingredients
IngredientUNIICASInChI Key
Indacaterol maleate2JEC1ITX7R753498-25-8IREJFXIHXRZFER-PCBAQXHCSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Arcapta NeohalerCapsule75 ug/1Oral; Respiratory (inhalation)Novartis2011-07-012018-08-31Us
Arcapta NeohalerCapsule75 ug/1Oral; Respiratory (inhalation)Sunovion2011-07-01Not applicableUs
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule300 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule300 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule150 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule300 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Hirobriz BreezhalerCapsule300 μgRespiratory (inhalation)Novartis Europharm Limited2009-11-30Not applicableEu
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Ultibro BreezhalerIndacaterol (110 mcg) + Glycopyrronium (50 mcg)CapsuleRespiratory (inhalation)Novartis2014-03-05Not applicableCanada
Utibron NeohalerIndacaterol maleate (27.5 ug/1) + Glycopyrronium bromide (15.6 ug/1)CapsuleRespiratory (inhalation)Sunovion2015-10-29Not applicableUs
Utibron NeohalerIndacaterol maleate (27.5 ug/1) + Glycopyrronium bromide (15.6 ug/1)CapsuleRespiratory (inhalation)Novartis2015-10-292019-06-30Us
International/Other Brands
Arcapta (Novartis) / Hirobriz / Onbrez (Novartis) / Onbrize
Categories
UNII
8OR09251MQ
CAS number
312753-06-3
Weight
Average: 392.4907
Monoisotopic: 392.209992772
Chemical Formula
C24H28N2O3
InChI Key
QZZUEBNBZAPZLX-QFIPXVFZSA-N
InChI
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
IUPAC Name
5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1,2-dihydroquinolin-2-one
SMILES
CCC1=C(CC)C=C2CC(CC2=C1)NC[C@H](O)C1=C2C=CC(=O)NC2=C(O)C=C1

Pharmacology

Indication

For the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Associated Conditions
Pharmacodynamics

Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are β(2) -agonists and anticholinergics, either alone or in combination. Currently available β(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting β(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Furthermore, this chiral compound it is given as the R-enantiomer and acts as a full agonist. Cough was the most commonly reported adverse effect with use of indacaterol. Compared to salmeterol, it has 35% more agonist activity. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. [PMID: 22499359]

Mechanism of action

Indacaterol works by stimulating adrenergic beta-2 receptors in the smooth muscle of the airways. This causes relaxation of the muscle, thereby increasing the diameter of the airways, which become constricted in asthma and COPD. It is also long acting due to its high affinity to the lipid raft domains in the airway membrane so it slowly dissociates from the receptors. Indacaterol also has a high intrinsic efficacy so it is also very rapid acting - onset of action occurs within 5 minutes.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Human
Absorption

The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%.

Volume of distribution

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution.

Protein binding

The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.

Metabolism

After oral administration of radiolabeled indacaterol, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. The monohydroxylated derivative, glucuronide conjugate, and the 8-O-glucuronide were the most prominent metabolites in serum. Other metabolites identified include a diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products.

In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol.

Route of elimination

Renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose).

Half life

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.

Clearance

Renal clearance of indacaterol is, on average, between 0.46 and 1.2 L/h. Serum clearance of indacaterol is 18.8 L/h to 23.3 L/h.

Toxicity

The expected signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Indacaterol.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Indacaterol.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Indacaterol.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Indacaterol.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Indacaterol.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Indacaterol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe risk or severity of adverse effects can be increased when 3-isobutyl-1-methyl-7H-xanthine is combined with Indacaterol.
3,4-MethylenedioxyamphetamineThe risk or severity of hypertension can be increased when 3,4-Methylenedioxyamphetamine is combined with Indacaterol.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Indacaterol.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Indacaterol.
Food Interactions
Not Available

References

General References
  1. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M: Effect of indacaterol, a novel long-acting beta2-agonist, on isolated human bronchi. Eur Respir J. 2007 Mar;29(3):575-81. Epub 2006 Nov 29. [PubMed:17135231]
  2. Kagan M, Dain J, Peng L, Reynolds C: Metabolism and pharmacokinetics of indacaterol in humans. Drug Metab Dispos. 2012 Sep;40(9):1712-22. doi: 10.1124/dmd.112.046151. Epub 2012 May 30. [PubMed:22648561]
  3. Reid DJ, Pham NT: Emerging Therapeutic Options for the Management of COPD. Clin Med Insights Circ Respir Pulm Med. 2013 Apr 9;7:7-15. doi: 10.4137/CCRPM.S8140. Print 2013. [PubMed:23641160]
External Links
Human Metabolome Database
HMDB0015608
KEGG Drug
D09318
PubChem Compound
6918554
PubChem Substance
175426936
ChemSpider
5293751
BindingDB
50318159
ChEBI
68575
ChEMBL
CHEMBL1095777
PharmGKB
PA165958348
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Indacaterol
ATC Codes
R03AL04 — Indacaterol and glycopyrronium bromideR03AC18 — Indacaterol
AHFS Codes
  • 12:12.08.12 — Selective Beta 2-adrenergic Agonists
FDA label
Download (360 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAsthma (Part 1) / COPD (Part 2)1
1CompletedTreatmentAsthma Bronchial1
1CompletedTreatmentAsthma Bronchial / Chronic Obstructive Pulmonary Disease (COPD)1
1CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Healthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHepatic Insufficiency1
1, 2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
2CompletedSupportive CareChronic Obstructive Pulmonary Disease (COPD)1
2CompletedTreatmentAsthma Bronchial8
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)8
2CompletedTreatmentPersistent Asthma1
2RecruitingTreatmentAsthma Bronchial1
2, 3CompletedTreatmentAsthma Bronchial1
2, 3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Lung Diseases, Obstructive / Pulmonary Disease, Chronic Obstructive2
3CompletedTreatmentAsthma Bronchial2
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)32
3CompletedTreatmentChronic Obstructive Pulmonary Disease: COPD1
3CompletedTreatmentPatients With Moderate-to-severe COPD With Destroyed Lung by Tuberculosis1
3CompletedTreatmentPulmonary Disease, Chronic Obstructive1
3RecruitingTreatmentCOPD (Chronic Obstructive Pulmonary Disease)1
3RecruitingTreatmentHeart Failure, Unspecified1
4CompletedBasic ScienceChronic Obstructive Pulmonary Disease (COPD) / Hyperinflation / Right Cardiac Failure1
4CompletedTreatmentAsthma Bronchial2
4CompletedTreatmentChronic Lung Diseases / Chronic Obstructive Pulmonary Disease (COPD) / Dyspnea / Hypoxemia / Tachycardia1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)12
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Healthy Volunteers1
4Not Yet RecruitingNot AvailableChronic Obstructive Pulmonary Disease (COPD)1
4Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4RecruitingOtherPulmonary Disease, Chronic Obstructive1
4RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)2
4WithdrawnTreatmentChronic Obstructive Pulmonary Disease (COPD)2
Not AvailableCompletedNot AvailableChronic Obstructive Pulmonary Disease (COPD)1
Not AvailableCompletedNot AvailablePulmonary Disease, Chronic Obstructive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral; Respiratory (inhalation)75 ug/1
CapsuleRespiratory (inhalation)75 mcg
CapsuleRespiratory (inhalation)150 μg
CapsuleRespiratory (inhalation)300 μg
CapsuleRespiratory (inhalation)
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6878721No2005-04-122020-10-10Us
US8067437No2011-11-292020-06-02Us
US8658673No2014-02-252020-06-02Us
US8796307No2014-08-052020-06-02Us
US8479730No2013-07-092028-10-11Us
US7229607No2007-06-122021-04-09Us
US7820694No2010-10-262020-06-02Us
US8029768No2011-10-042021-04-09Us
US8283362No2012-10-092020-06-02Us
US7736670No2010-06-152021-06-27Us
US8435567No2013-05-072021-06-27Us
US8303991No2012-11-062021-06-27Us
US8956661No2015-02-172021-06-27Us
US8580306No2013-11-122021-06-27Us
US6582678No2003-06-242018-04-24Us
US8182838No2012-05-222028-10-20Us
US6521260No2003-02-182016-01-31Us
US8048451No2011-11-012021-06-27Us
US9931304No2018-04-032021-06-27Us
US9962338No2018-05-082021-06-27Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)195-202°C with decompositionNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00798 mg/mLALOGPS
logP3.31ALOGPS
logP3.26ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)8.51ChemAxon
pKa (Strongest Basic)9.71ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area81.59 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity118.1 m3·mol-1ChemAxon
Polarizability44.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9963
Blood Brain Barrier+0.5
Caco-2 permeable-0.6288
P-glycoprotein substrateSubstrate0.6953
P-glycoprotein inhibitor INon-inhibitor0.9284
P-glycoprotein inhibitor IINon-inhibitor0.9178
Renal organic cation transporterNon-inhibitor0.8838
CYP450 2C9 substrateNon-substrate0.8148
CYP450 2D6 substrateNon-substrate0.6907
CYP450 3A4 substrateSubstrate0.5896
CYP450 1A2 substrateInhibitor0.553
CYP450 2C9 inhibitorNon-inhibitor0.56
CYP450 2D6 inhibitorNon-inhibitor0.8547
CYP450 2C19 inhibitorNon-inhibitor0.5581
CYP450 3A4 inhibitorNon-inhibitor0.6546
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5888
Ames testNon AMES toxic0.7577
CarcinogenicityNon-carcinogens0.8559
BiodegradationNot ready biodegradable0.9856
Rat acute toxicity2.6531 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9657
hERG inhibition (predictor II)Inhibitor0.6406
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as hydroxyquinolones. These are compounds containing a quinoline moiety bearing a hydroxyl group and a ketone. Quinoline or benzo[b]pyridine is a bicyclic compound that consists of benzene fused to a pyridine.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Quinolones and derivatives
Direct Parent
Hydroxyquinolones
Alternative Parents
8-hydroxyquinolines / Hydroxyquinolines / Hydroquinolones / Hydroquinolines / Indanes / 1-hydroxy-2-unsubstituted benzenoids / Pyridinones / Aralkylamines / Heteroaromatic compounds / 1,2-aminoalcohols
show 8 more
Substituents
Hydroxyquinolone / Dihydroquinolone / Hydroxyquinoline / 8-hydroxyquinoline / Dihydroquinoline / Indane / 1-hydroxy-2-unsubstituted benzenoid / Pyridinone / Aralkylamine / Benzenoid
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
secondary alcohol, secondary amino compound, indanes, quinolone, monohydroxyquinoline (CHEBI:68575)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately ...
Gene Name
ADRB2
Uniprot ID
P07550
Uniprot Name
Beta-2 adrenergic receptor
Molecular Weight
46458.32 Da
References
  1. Cazzola M, Matera MG, Lotvall J: Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2005 Jul;14(7):775-83. [PubMed:16022567]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 21, 2007 16:23 / Updated on December 14, 2018 17:10