N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino}ethyl]phenyl}formamide

• ChemBase ID: 1137
• Molecular Formular: C19H24N2O4
• Molecular Mass: 344.40486
• Monoisotopic Mass: 344.17360726
• SMILES: O[C@@H](CN[C@@H](Cc1ccc(OC)cc1)C)c1cc(NC=O)c(O)cc1
• Canonical SMILES: O=CNc1cc(ccc1O)[C@H](CN[C@@H](Cc1ccc(cc1)OC)C)O
• 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
• InChIKey: BPZSYCZIITTYBL-YJYMSZOUSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino}ethyl]phenyl}formamide
• IUPAC Traditional name: formoterol; arformoterol
• Brand Name: Brovana; Foradil/Foradile (Schering-Plough in the U.S., Novartis rest of world), Oxeze/Oxis (AstraZeneca), Atock (Astellas), Atimos/Atimos Modulite (Chiesi), and Perforomist (Dey)
• Synonyms: (R,R)-formoterol; arformoterol; Arformoterol; Formoterol

Database IDs

• CAS Number: 73573-87-2; 67346-49-0
• PubChem SID: 160964600; 46506392
• PubChem CID: 3083544
• CHEBI ID: 408174
• ATC CODE: R03AC13
• CHEMBL: 1363
• Chemspider ID: 2340731
• DrugBank ID: DB00983
• IUPHAR ligand ID: 3465
• KEGG ID: D07990
• Unique Ingredient Identifier: 5ZZ84GCW8B
• Wikipedia Title: Formoterol

CALCULATED PROPERTIES

JChem

• Acid pKa: 8.607353
• H Acceptors: 5
• H Donor: 4
• LogD (pH = 5.5): -1.1008605
• LogD (pH = 7.4): 0.03789571
• Log P: 1.0566727
• Molar Refractivity: 97.8715 cm^3
• Polarizability: 37.3542 Å^3
• Polar Surface Area: 90.82 Å^2
• Rotatable Bonds: 8
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.91
• LOG S: -3.92
• Solubility (Water): 4.16e-02 g/l

PROPERTIES

Physical Property

• Hydrophobicity(logP): 2.2

Pharmacology Properties

• Admin Routes: Oral, Inhalation
• Excretion: Renal and fecal
• Half Life: 10 hours
• Metabolism: Hepatic demethylation and glucuronidation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6 involved)
• Protein Bound: 61–64%
• Legal Status: POM (UK); Rx-only (US)
• Pregnancy Category: B3 (Australia); C (US)

DETAILS

DrugBank - DB01274

• Drug 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.
• 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.
• Pharmacology: 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.
• 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
• Biotransformation: 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.
• 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.
• 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.
• 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.
• Clearance: * renal cl=8.9 L/hr [Healthy male subjects]
• References: 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. [Pubmed] ; 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. [Pubmed] ; 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] ; 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. [Pubmed] ; 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. Epub 2008 Apr 7. [Pubmed] ; 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]
• External Links: RxList; Drugs.com

REFERENCES

• 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. Pubmed
• 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. Pubmed
• 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
• 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. Pubmed
• 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. Epub 2008 Apr 7. Pubmed
• 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