Identification

Name
Arformoterol
Accession Number
DB01274
Type
Small Molecule
Groups
Approved, Investigational
Description

Arformoterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Arformoterol inhalation is used to prevent bronchoconstriction in people with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The use of arformoterol is pending revision due to safety concerns in regards to an increased risk of severe exacerbation of asthma symptoms, leading to hospitalization as well as death in some patients using long acting beta agonists for the treatment of asthma.

Structure
Thumb
Synonyms
  • (-)-Formoterol
  • (R,R)-formoterol
Product Ingredients
IngredientUNIICASInChI Key
Arformoterol tartrate5P8VJ2I235200815-49-2FCSXYHUNDAXDRH-OKMNHOJOSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BrovanaSolution15 ug/2mLRespiratory (inhalation)Sunovion2007-04-01Not applicableUs
Categories
UNII
F91H02EBWT
CAS number
67346-49-0
Weight
Average: 344.4049
Monoisotopic: 344.173607266
Chemical Formula
C19H24N2O4
InChI Key
BPZSYCZIITTYBL-YJYMSZOUSA-N
InChI
InChI=1S/C19H24N2O4/c1-13(9-14-3-6-16(25-2)7-4-14)20-11-19(24)15-5-8-18(23)17(10-15)21-12-22/h3-8,10,12-13,19-20,23-24H,9,11H2,1-2H3,(H,21,22)/t13-,19+/m1/s1
IUPAC Name
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino}ethyl]phenyl}formamide
SMILES
COC1=CC=C(C[C@@H](C)NC[C@H](O)C2=CC(NC=O)=C(O)C=C2)C=C1

Pharmacology

Indication

A bronchodilator used for the long term, symptomatic treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Associated Conditions
Pharmacodynamics

Arformoterol, the active (R,R)-enantiomer of formoterol, is a selective long-acting β2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a β2-agonist than the (R,R)-enantiomer. Arformoterol seems to have little or no effect on β1-adrenergic receptors.

Mechanism of action

While it is recognized that β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, data indicate that there are also β2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects. The pharmacologic effects of β2-adrenoceptor agonist drugs, including arformoterol, 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 AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of proinflammatory mediators from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-response.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol.

Metabolism

Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19.

Route of elimination

After administration of a single oral dose of radiolabeled arformoterol to eight healthy male subjects, 63% of the total radioactive dose was recovered in urine and 11% in feces within 48 hours. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route.

Half life

In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours.

Clearance
  • renal cl=8.9 L/hr [Healthy male subjects]
Toxicity

A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose.

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

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Arformoterol.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Arformoterol.
AbacavirAbacavir may decrease the excretion rate of Arformoterol which could result in a higher serum level.
AbediterolThe risk or severity of adverse effects can be increased when Arformoterol is combined with Abediterol.
AbexinostatThe risk or severity of QTc prolongation can be increased when Arformoterol is combined with Abexinostat.
AbirateroneThe metabolism of Arformoterol can be decreased when combined with Abiraterone.
AcarboseAcarbose may decrease the excretion rate of Arformoterol which could result in a higher serum level.
AcebutololThe therapeutic efficacy of Arformoterol can be decreased when used in combination with Acebutolol.
AceclofenacAceclofenac may decrease the excretion rate of Arformoterol which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Arformoterol which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

Vaman Vaishali Haldavanekar, Mangesh Prabhu, Dharmaraj Ramachandra Rao, Rajendra Narayanrao Kankan, "Process for the Synthesis of Arformoterol." U.S. Patent US20110166237, issued July 07, 2011.

US20110166237
General References
  1. Hanania NA, Donohue JF, Nelson H, Sciarappa K, Goodwin E, Baumgartner RA, Hanrahan JP: The safety and efficacy of arformoterol and formoterol in COPD. COPD. 2010 Feb;7(1):17-31. doi: 10.3109/15412550903499498. [PubMed:20214460]
  2. Donohue JF, Hanania NA, Sciarappa KA, Goodwin E, Grogan DR, Baumgartner RA, Hanrahan JP: Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: a one year evaluation of safety and tolerance. Ther Adv Respir Dis. 2008 Apr;2(2):37-48. doi: 10.1177/1753465808089455. [PubMed:19124357]
  3. 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]
  4. Panettieri RA Jr, MacIntyre N, Sims M, Kerwin E, Fogarty C, Noonan M, Claus R, Andrews WT: Comparison of the efficacy and safety of arformoterol 15 microg twice daily and arformoterol 30 microg once daily in COPD: a single-dose, multicenter, randomized, modified-blind, two-way crossover study. Clin Ther. 2009 Aug;31(8):1716-23. doi: 10.1016/j.clinthera.2009.08.012. [PubMed:19808130]
  5. Kharidia J, Fogarty CM, Laforce CF, Maier G, Hsu R, Dunnington KM, Curry L, Baumgartner RA, Hanrahan JP: A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008 Aug;21(4):657-62. doi: 10.1016/j.pupt.2008.03.003. Epub 2008 Apr 7. [PubMed:18501650]
  6. Baumgartner RA, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Hanrahan JP: Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Clin Ther. 2007 Feb;29(2):261-78. [PubMed:17472819]
External Links
Human Metabolome Database
HMDB0015399
PubChem Compound
3083544
PubChem Substance
46506392
ChemSpider
2340731
BindingDB
50151720
ChEBI
408174
ChEMBL
CHEMBL1363
Therapeutic Targets Database
DAP000943
PharmGKB
PA164743977
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Arformoterol

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAsthma Bronchial1
2CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3CompletedTreatmentBronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema1
3CompletedTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema2
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)2
3WithdrawnPreventionExercise-Induced Bronchoconstriction (EIB)1
4CompletedTreatmentBronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)3
4RecruitingTreatmentAcute Exacerbation of Chronic Obstructive Pulmonary Disease / Chronic Obstructive Pulmonary Disease (COPD)1
4TerminatedTreatmentAsthma Acute1
4TerminatedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4Unknown StatusTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema1
Not AvailableCompletedDiagnosticChronic Obstructive Pulmonary Disease (COPD)1
Not AvailableCompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Cardinal Health
  • Catalent Pharma Solutions
  • Sepracor Pharmaceuticals Inc.
Dosage forms
FormRouteStrength
SolutionRespiratory (inhalation)15 ug/2mL
Prices
Unit descriptionCostUnit
Brovana 15 mcg/2 ml solution3.41USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5795564No1998-08-182012-04-03Us
US6814953No2004-11-092021-06-22Us
US7348362No2008-03-252021-06-22Us
US7462645No2008-12-092021-06-22Us
US7473710No2009-01-062021-06-22Us
US7541385No2009-06-022021-06-22Us
US6667344No2003-12-232021-06-22Us
US6040344No2000-03-212016-11-12Us
US8110706No2012-02-072021-11-09Us
US7465756No2008-12-162021-06-22Us
US6720453No2004-04-132021-11-09Us
US6472563No2002-10-292021-11-09Us
US7145036No2006-12-052021-11-09Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0416 mg/mLALOGPS
logP1.91ALOGPS
logP1.06ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)8.61ChemAxon
pKa (Strongest Basic)9.81ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area90.82 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity97.87 m3·mol-1ChemAxon
Polarizability36.56 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8991
Blood Brain Barrier-0.8026
Caco-2 permeable-0.6916
P-glycoprotein substrateSubstrate0.747
P-glycoprotein inhibitor INon-inhibitor0.8773
P-glycoprotein inhibitor IINon-inhibitor0.8561
Renal organic cation transporterNon-inhibitor0.8818
CYP450 2C9 substrateNon-substrate0.714
CYP450 2D6 substrateNon-substrate0.7086
CYP450 3A4 substrateSubstrate0.5556
CYP450 1A2 substrateNon-inhibitor0.6609
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorInhibitor0.8994
CYP450 3A4 inhibitorNon-inhibitor0.8757
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8442
Ames testNon AMES toxic0.7517
CarcinogenicityNon-carcinogens0.8704
BiodegradationNot ready biodegradable0.992
Rat acute toxicity2.4047 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9611
hERG inhibition (predictor II)Non-inhibitor0.6602
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 amphetamines and derivatives. These are organic compounds containing or derived from 1-phenylpropan-2-amine.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenethylamines
Direct Parent
Amphetamines and derivatives
Alternative Parents
Phenylpropanes / Anilides / Phenoxy compounds / N-arylamides / Methoxybenzenes / Anisoles / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Secondary carboxylic acid amides
show 9 more
Substituents
Amphetamine or derivatives / Phenylpropane / Anilide / Phenoxy compound / Anisole / Phenol ether / N-arylamide / Methoxybenzene / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid
show 23 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
N-[2-hydroxy-5-(1-hydroxy-2-\{[1-(4-methoxyphenyl)propan-2-yl]amino\}ethyl)phenyl]formamide (CHEBI:408174)

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. Authors unspecified: Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol. Drugs R D. 2004;5(1):25-7. [PubMed:14725487]
  2. Op't Holt TB: Inhaled beta agonists. Respir Care. 2007 Jul;52(7):820-32. [PubMed:17594727]
  3. Matera MG, Cazzola M: ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs. 2007;67(4):503-15. [PubMed:17352511]
  4. Cazzola M, Hanania NA, Matera MG: Arformoterol tartrate in the treatment of COPD. Expert Rev Respir Med. 2010 Apr;4(2):155-62. doi: 10.1586/ers.10.16. [PubMed:20406080]
  5. 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]
  6. Kharidia J, Fogarty CM, Laforce CF, Maier G, Hsu R, Dunnington KM, Curry L, Baumgartner RA, Hanrahan JP: A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2008 Aug;21(4):657-62. doi: 10.1016/j.pupt.2008.03.003. Epub 2008 Apr 7. [PubMed:18501650]
  7. Baumgartner RA, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Hanrahan JP: Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. Clin Ther. 2007 Feb;29(2):261-78. [PubMed:17472819]
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR: A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805. Epub 2007 Jul 12. [PubMed:17627976]
  2. Zhang M, Fawcett JP, Kennedy JM, Shaw JP: Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol. 2000 Feb;49(2):152-7. [PubMed:10671910]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR: A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805. Epub 2007 Jul 12. [PubMed:17627976]
  2. Zhang M, Fawcett JP, Kennedy JM, Shaw JP: Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol. 2000 Feb;49(2):152-7. [PubMed:10671910]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR: A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805. Epub 2007 Jul 12. [PubMed:17627976]
  2. Zhang M, Fawcett JP, Kennedy JM, Shaw JP: Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol. 2000 Feb;49(2):152-7. [PubMed:10671910]
  3. Formoterol FDA Label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR: A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805. Epub 2007 Jul 12. [PubMed:17627976]
  2. Zhang M, Fawcett JP, Kennedy JM, Shaw JP: Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol. 2000 Feb;49(2):152-7. [PubMed:10671910]
  3. Formoterol FDA Label [File]

Drug created on May 16, 2007 14:28 / Updated on November 02, 2018 08:51