You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameIndacaterol
Accession NumberDB05039
TypeSmall Molecule
GroupsApproved
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
5-(2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl)-8-hydroxy-1H-quinolin-2-one
QAB 149
QAB-149
QAB149
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Arcapta Neohalercapsule75 ug/1oral; respiratory (inhalation)Novartis Pharmaceuticals Corporation2011-07-01Not applicableUs
Onbrez Breezhalercapsule75 mcginhalationNovartis Pharmaceuticals Canada Inc2012-03-05Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
Arcapta Novartis
HirobrizNot Available
OnbrezNovartis
Onbrize Not Available
Brand mixtures
NameLabellerIngredients
Ultibro BreezhalerNovartis Pharmaceuticals Canada Inc
Utibron NeohalerNovartis Pharmaceuticals Corporation
Salts
Name/CASStructureProperties
Indacaterol Maleate
753498-25-8
Thumb
  • InChI Key: IREJFXIHXRZFER-PCBAQXHCSA-N
  • Monoisotopic Mass: 508.220951388
  • Average Mass: 508.5629
DBSALT000101
Categories
UNII8OR09251MQ
CAS number312753-06-3
WeightAverage: 392.4907
Monoisotopic: 392.209992772
Chemical FormulaC24H28N2O3
InChI KeyInChIKey=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[[email protected]](O)C1=C2C=CC(=O)NC2=C(O)C=C1
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassQuinolines and derivatives
Sub ClassQuinolones and derivatives
Direct ParentHydroxyquinolones
Alternative Parents
Substituents
  • Hydroxyquinolone
  • 8-hydroxyquinoline
  • Hydroxyquinoline
  • Dihydroquinolone
  • Dihydroquinoline
  • Indane
  • Aralkylamine
  • Pyridinone
  • Benzenoid
  • Pyridine
  • Heteroaromatic compound
  • Secondary alcohol
  • Lactam
  • 1,2-aminoalcohol
  • Azacycle
  • Secondary amine
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Aromatic alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the long term, once-daily-dosing maintenance of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
PharmacodynamicsBronchodilator 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 actionIndacaterol 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.
Related Articles
AbsorptionThe 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 bindingThe 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.

SubstrateEnzymesProduct
Indacaterol
Not Available
8-O-glucuronideDetails
Route of eliminationRenal 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 lifeIndacaterol 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.

ToxicityThe 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral; respiratory (inhalation)75 ug/1
Capsuleinhalation75 mcg
Kit; capsuleinhalation
Capsulerespiratory (inhalation)
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6521260 No1996-01-312016-01-31Us
US6582678 No1998-04-242018-04-24Us
US6878721 No2000-10-102020-10-10Us
US7229607 No2001-04-092021-04-09Us
US7736670 No2001-06-272021-06-27Us
US7820694 No2000-06-022020-06-02Us
US8029768 No2001-04-092021-04-09Us
US8048451 No2001-06-272021-06-27Us
US8067437 No2000-06-022020-06-02Us
US8182838 No2008-10-202028-10-20Us
US8283362 No2000-06-022020-06-02Us
US8303991 No2001-06-272021-06-27Us
US8435567 No2001-06-272021-06-27Us
US8479730 No2008-10-112028-10-11Us
US8580306 No2001-06-272021-06-27Us
US8658673 No2000-06-022020-06-02Us
US8796307 No2000-06-022020-06-02Us
US8956661 No2001-06-272021-06-27Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point195-202°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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesR03AC18R03AL04
AHFS Codes
  • 12:12.08.12
PDB EntriesNot Available
FDA labelDownload (360 KB)
MSDSDownload (479 KB)
Interactions
Drug Interactions
Drug
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Indacaterol.
AminophyllineThe risk or severity of adverse effects can be increased when Aminophylline is combined with Indacaterol.
AmitriptylineThe risk or severity of adverse effects can be increased when Amitriptyline is combined with Indacaterol.
AmphetamineThe risk or severity of adverse effects can be increased when Amphetamine is combined with Indacaterol.
AtomoxetineAtomoxetine may increase the tachycardic activities of Indacaterol.
AtosibanThe risk or severity of adverse effects can be increased when Indacaterol is combined with Atosiban.
BenzphetamineThe risk or severity of adverse effects can be increased when Benzphetamine is combined with Indacaterol.
BetahistineThe therapeutic efficacy of Indacaterol can be decreased when used in combination with Betahistine.
BetamethasoneIndacaterol may increase the hypokalemic activities of Betamethasone.
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Indacaterol.
ChlorphentermineThe risk or severity of adverse effects can be increased when Chlorphentermine is combined with Indacaterol.
CitalopramIndacaterol may increase the QTc-prolonging activities of Citalopram.
ClenbuterolThe risk or severity of adverse effects can be increased when Clenbuterol is combined with Indacaterol.
CorticotropinIndacaterol may increase the hypokalemic activities of Corticotropin.
Cortisone acetateIndacaterol may increase the hypokalemic activities of Cortisone acetate.
DexamethasoneIndacaterol may increase the hypokalemic activities of Dexamethasone.
DobutamineThe risk or severity of adverse effects can be increased when Dobutamine is combined with Indacaterol.
DofetilideIndacaterol may increase the QTc-prolonging activities of Dofetilide.
DopamineThe risk or severity of adverse effects can be increased when Dopamine is combined with Indacaterol.
DoxofyllineThe risk or severity of adverse effects can be increased when Indacaterol is combined with Doxofylline.
DronabinolDronabinol may increase the tachycardic activities of Indacaterol.
DyphyllineThe risk or severity of adverse effects can be increased when Dyphylline is combined with Indacaterol.
EpinephrineThe risk or severity of adverse effects can be increased when Epinephrine is combined with Indacaterol.
EsmololEsmolol may decrease the activities of Indacaterol.
FenoterolThe risk or severity of adverse effects can be increased when Fenoterol is combined with Indacaterol.
FludrocortisoneIndacaterol may increase the hypokalemic activities of Fludrocortisone.
FormoterolThe risk or severity of adverse effects can be increased when Formoterol is combined with Indacaterol.
GoserelinIndacaterol may increase the QTc-prolonging activities of Goserelin.
HydrocortisoneIndacaterol may increase the hypokalemic activities of Hydrocortisone.
IobenguaneThe therapeutic efficacy of Iobenguane can be decreased when used in combination with Indacaterol.
IsoprenalineThe risk or severity of adverse effects can be increased when Isoprenaline is combined with Indacaterol.
LabetalolThe risk or severity of adverse effects can be increased when Labetalol is combined with Indacaterol.
LeuprolideIndacaterol may increase the QTc-prolonging activities of Leuprolide.
LinezolidLinezolid may increase the hypertensive activities of Indacaterol.
LoxapineThe risk or severity of adverse effects can be increased when Indacaterol is combined with Loxapine.
MephentermineThe risk or severity of adverse effects can be increased when Mephentermine is combined with Indacaterol.
MetaraminolThe risk or severity of adverse effects can be increased when Metaraminol is combined with Indacaterol.
MethamphetamineThe risk or severity of adverse effects can be increased when Methamphetamine is combined with Indacaterol.
MethoxamineThe risk or severity of adverse effects can be increased when Methoxamine is combined with Indacaterol.
MethylprednisoloneIndacaterol may increase the hypokalemic activities of Methylprednisolone.
MidodrineThe risk or severity of adverse effects can be increased when Midodrine is combined with Indacaterol.
MifepristoneMifepristone may increase the QTc-prolonging activities of Indacaterol.
NadololNadolol may decrease the activities of Indacaterol.
NaphazolineThe risk or severity of adverse effects can be increased when Naphazoline is combined with Indacaterol.
NorepinephrineThe risk or severity of adverse effects can be increased when Norepinephrine is combined with Indacaterol.
OrciprenalineThe risk or severity of adverse effects can be increased when Orciprenaline is combined with Indacaterol.
OxymetazolineThe risk or severity of adverse effects can be increased when Oxymetazoline is combined with Indacaterol.
PhenelzineThe risk or severity of adverse effects can be increased when Phenelzine is combined with Indacaterol.
PhenmetrazineThe risk or severity of adverse effects can be increased when Phenmetrazine is combined with Indacaterol.
PhentermineThe risk or severity of adverse effects can be increased when Phentermine is combined with Indacaterol.
PhenylephrineThe risk or severity of adverse effects can be increased when Phenylephrine is combined with Indacaterol.
PhenylpropanolamineThe risk or severity of adverse effects can be increased when Phenylpropanolamine is combined with Indacaterol.
PrednisoloneIndacaterol may increase the hypokalemic activities of Prednisolone.
PrednisoneIndacaterol may increase the hypokalemic activities of Prednisone.
Repository corticotropinIndacaterol may increase the hypokalemic activities of Repository corticotropin.
RitodrineThe risk or severity of adverse effects can be increased when Ritodrine is combined with Indacaterol.
SalmeterolThe risk or severity of adverse effects can be increased when Salmeterol is combined with Indacaterol.
Tedizolid PhosphateTedizolid Phosphate may increase the hypertensive activities of Indacaterol.
TerbutalineThe risk or severity of adverse effects can be increased when Terbutaline is combined with Indacaterol.
TheophyllineThe risk or severity of adverse effects can be increased when Theophylline is combined with Indacaterol.
TorasemideIndacaterol may increase the hypokalemic activities of Torasemide.
TranylcypromineThe risk or severity of adverse effects can be increased when Tranylcypromine is combined with Indacaterol.
TriamcinoloneIndacaterol may increase the hypokalemic activities of Triamcinolone.
TrichlormethiazideIndacaterol may increase the hypokalemic activities of Trichlormethiazide.
Food InteractionsNot Available

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 30-fold greater affinity than it does norepinephrine.
Gene Name:
ADRB2
Uniprot ID:
P07550
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
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 IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naph...
Gene Name:
UGT1A1
Uniprot ID:
P22309
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
Molecular Weight:
141477.255 Da
Comments
comments powered by Disqus
Drug created on October 21, 2007 16:23 / Updated on June 26, 2016 01:53