Identification

Name
Olodaterol
Accession Number
DB09080
Type
Small Molecule
Groups
Approved
Description

Olodaterol is a novel, long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. It is by this mechanism that olodaterol is used for the treatment of chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that is characteristic of it. Treatment with bronchodilators helps to mitigate associated symptoms such as shortness of breath, cough, and sputum production. Single doses of olodaterol have been shown to improve forced expiratory volume in 1 sec (FEV1) for 24 h in patients with COPD, allowing once daily dosing. A once-a-day treatment with a LABA has several advantages over short-acting bronchodilators and twice-daily LABAs including improved convenience and compliance and improved airflow over a 24-hour period. Despite similarities in symptoms, olodaterol is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Structure
Thumb
Synonyms
Not Available
External IDs
BI 1744 / BI-1744 / BI1744
Product Ingredients
IngredientUNIICASInChI Key
Olodaterol hydrochloride65R445W3V9869477-96-3KCEHVJZZIGJAAW-FERBBOLQSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Striverdi RespimatSolution2.5 mcgRespiratory (inhalation)Boehringer Ingelheim (Canada) Ltd LteeNot applicableNot applicableCanada
Striverdi RespimatSpray, metered2.5 ug/1Respiratory (inhalation)Boehringer Ingelheim2014-08-01Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Inspiolto RespimatOlodaterol hydrochloride (2.5 mcg) + Tiotropium (2.5 mcg)SolutionRespiratory (inhalation)Boehringer Ingelheim (Canada) Ltd Ltee2015-05-29Not applicableCanada
Stiolto RespimatOlodaterol hydrochloride (2.736 ug/1) + Tiotropium bromide monohydrate (3.124 ug/1)Spray, meteredRespiratory (inhalation)Boehringer Ingelheim2015-05-21Not applicableUs
Categories
UNII
VD2YSN1AFD
CAS number
868049-49-4
Weight
Average: 386.448
Monoisotopic: 386.184171945
Chemical Formula
C21H26N2O5
InChI Key
COUYJEVMBVSIHV-SFHVURJKSA-N
InChI
InChI=1S/C21H26N2O5/c1-21(2,10-13-4-6-15(27-3)7-5-13)22-11-18(25)16-8-14(24)9-17-20(16)28-12-19(26)23-17/h4-9,18,22,24-25H,10-12H2,1-3H3,(H,23,26)/t18-/m0/s1
IUPAC Name
6-hydroxy-8-[(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl]-3,4-dihydro-2H-1,4-benzoxazin-3-one
SMILES
COC1=CC=C(CC(C)(C)NC[C@H](O)C2=C3OCC(=O)NC3=CC(O)=C2)C=C1

Pharmacology

Indication

Olodaterol is indicated for use in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Associated Conditions
Pharmacodynamics

Olodaterol is a potent agonist of the human beta2-adrenergic receptor in vitro, and is highly selective for this receptor, with much lower levels of activity at the b1- and b3-adrenergic receptors that are commonly expressed on cardiac smooth muscle and adipose tissue, respectively. Binding to the receptor causes smooth muscle relaxation in the lungs and bronchodilation. It has also been shown to potently reverse active bronchoconstriction.

Mechanism of action

Olodaterol is a long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Human
Absorption

Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.

Volume of distribution

The volume of distribution is high (1110 L), suggesting extensive distribution into tissue.

Protein binding

In vitro binding of olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

Metabolism

Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.

Route of elimination

Following intravenous administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%).

Half life

The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes.

Clearance

Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min.

Toxicity

Adverse drug reactions that occurred at a frequency greater than 2% include nasopharyngitis (11.3%), upper respiratory tract infection (8.2%), bronchitis (4.7%), urinary tract infection (2.5%), cough (4.2%), dizziness (2.3%), rash (2.2%), diarrhea (2.9%), back pain (3.5%), and arthralgia (2.1%).

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Olodaterol.
AbirateroneThe serum concentration of Olodaterol can be increased when it is combined with Abiraterone.
AcebutololThe therapeutic efficacy of Olodaterol can be decreased when used in combination with Acebutolol.
AcepromazineAcepromazine may decrease the vasoconstricting activities of Olodaterol.
Acetyl sulfisoxazoleThe metabolism of Olodaterol can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe risk or severity of hypokalemia can be increased when Alclometasone is combined with Olodaterol.
AlfuzosinThe therapeutic efficacy of Olodaterol can be decreased when used in combination with Alfuzosin.
AlimemazineThe risk or severity of QTc prolongation can be increased when Olodaterol is combined with Alimemazine.
AlprenololAlprenolol may decrease the bronchodilatory activities of Olodaterol.
Ambroxol acefyllinateThe risk or severity of adverse effects can be increased when Ambroxol acefyllinate is combined with Olodaterol.
Food Interactions
Not Available

References

General References
  1. Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A: Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010 Jul;334(1):53-62. doi: 10.1124/jpet.110.167007. Epub 2010 Apr 6. [PubMed:20371707]
  2. Bouyssou T, Hoenke C, Rudolf K, Lustenberger P, Pestel S, Sieger P, Lotz R, Heine C, Buttner FH, Schnapp A, Konetzki I: Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett. 2010 Feb 15;20(4):1410-4. doi: 10.1016/j.bmcl.2009.12.087. Epub 2010 Jan 4. [PubMed:20096576]
  3. Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo MC, Paggiaro P: Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat(R) versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014 Jul 5;9:697-714. doi: 10.2147/COPD.S62502. eCollection 2014. [PubMed:25045258]
  4. Gibb A, Yang LP: Olodaterol: first global approval. Drugs. 2013 Nov;73(16):1841-6. doi: 10.1007/s40265-013-0137-9. [PubMed:24158691]
  5. Deeks ED: Olodaterol: a review of its use in chronic obstructive pulmonary disease. Drugs. 2015 Apr;75(6):665-73. doi: 10.1007/s40265-015-0371-4. [PubMed:25773742]
External Links
KEGG Drug
D10145
PubChem Compound
11504295
PubChem Substance
310265008
ChemSpider
9679097
ChEBI
82700
ChEMBL
CHEMBL605846
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Olodaterol
ATC Codes
R03AL06 — Olodaterol and tiotropium bromideR03AC19 — Olodaterol
AHFS Codes
  • 12:12.08.12 — Selective Beta 2-adrenergic Agonists
FDA label
Download (746 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers / Pulmonary Disease, Chronic Obstructive2
1CompletedTreatmentPulmonary Disease, Chronic Obstructive2
2CompletedTreatmentAsthma Bronchial2
2CompletedTreatmentPulmonary Disease, Chronic Obstructive3
2WithdrawnTreatmentAsthma Bronchial1
3CompletedTreatmentPulmonary Disease, Chronic Obstructive25
4Active Not RecruitingTreatmentPulmonary Disease, Chronic Obstructive1
4CompletedBasic ScienceChronic Obstructive Pulmonary Disease (COPD)1
4CompletedTreatmentPulmonary Disease, Chronic Obstructive2
4Not Yet RecruitingOtherPulmonary Disease, Chronic Obstructive1
4RecruitingBasic ScienceChronic Obstructive Pulmonary Disease (COPD)1
4RecruitingTreatmentAsthma Bronchial1
4RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4RecruitingTreatmentPulmonary Disease, Chronic Obstructive2
Not AvailableCompletedNot AvailablePulmonary Disease, Chronic Obstructive1
Not AvailableRecruitingNot AvailablePulmonary Disease, Chronic Obstructive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionRespiratory (inhalation)
Spray, meteredRespiratory (inhalation)
SolutionRespiratory (inhalation)2.5 mcg
Spray, meteredRespiratory (inhalation)2.5 ug/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
USRE39820Yes1998-07-302018-07-30Us
US6453795Yes1997-06-052017-06-05Us
US8733341Yes2011-04-162031-04-16Us
US9027967Yes2007-10-012027-10-01Us
US7104470Yes1997-04-042017-04-04Us
US7246615Yes1996-12-012016-12-01Us
US7896264Yes2005-11-262025-11-26Us
US7988001Yes2002-02-042022-02-04Us
US7802568Yes1999-08-262019-08-26Us
US6149054Yes1997-06-162017-06-16Us
US6726124Yes1997-04-042017-04-04Us
US7396341Yes2007-04-102027-04-10Us
US6846413Yes1999-02-282019-02-28Us
US6176442Yes1996-12-012016-12-01Us
US7837235Yes2008-09-132028-09-13Us
US5964416Yes1997-04-042017-04-04Us
US7284474Yes2005-02-262025-02-26Us
US6977042Yes1999-02-282019-02-28Us
US6988496Yes2000-08-232020-08-23Us
US8044046No2003-11-102023-11-10Us
US8034809No2005-05-122025-05-12Us
US7220742No2005-05-122025-05-12Us
US7491719No2003-11-102023-11-10Us
US7056916No2003-12-072023-12-07Us
US7727984No2003-11-102023-11-10Us
US7786111No2003-11-102023-11-10Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0703 mg/mLALOGPS
logP2.02ALOGPS
logP1.19ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)9.22ChemAxon
pKa (Strongest Basic)9.84ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area100.05 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity106.9 m3·mol-1ChemAxon
Polarizability41.34 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 benzoxazinones. These are organic compounds containing a benzene fused to an oxazine ring (a six-member aliphatic ring with four carbon atoms, one oxygen atom, and one nitrogen atom) bearing a ketone group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzoxazines
Sub Class
Benzoxazinones
Direct Parent
Benzoxazinones
Alternative Parents
Amphetamines and derivatives / Benzomorpholines / Phenylpropanes / Phenoxy compounds / Methoxybenzenes / Anisoles / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Secondary carboxylic acid amides
show 12 more
Substituents
Benzoxazinone / Amphetamine or derivatives / Benzomorpholine / Phenylpropane / Anisole / Phenoxy compound / Phenol ether / Methoxybenzene / Aralkylamine / 1-hydroxy-2-unsubstituted benzenoid
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, secondary alcohol, phenols, secondary amino compound, benzoxazine (CHEBI:82700)

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. Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A: Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010 Jul;334(1):53-62. doi: 10.1124/jpet.110.167007. Epub 2010 Apr 6. [PubMed:20371707]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
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
Kind
Protein
Organism
Human
Pharmacological action
No
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da

Drug created on June 26, 2015 12:38 / Updated on September 23, 2018 19:37