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Also known as: 89365-50-4, Serevent, Astmerole, Aeromax, Salmeterolum [latin], 2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol
Molecular Formula
C25H37NO4
Molecular Weight
415.6  g/mol
InChI Key
GIIZNNXWQWCKIB-UHFFFAOYSA-N
FDA UNII
2I4BC502BT

CAS 89365-50-4
A selective ADRENERGIC BETA-2 RECEPTOR agonist that functions as a BRONCHODILATOR when administered by inhalation. It is used to manage the symptoms of ASTHMA and CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
Salmeterol is a beta2-Adrenergic Agonist. The mechanism of action of salmeterol is as an Adrenergic beta2-Agonist.
1 2D Structure

CAS 89365-50-4

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol
2.1.2 InChI
InChI=1S/C25H37NO4/c27-20-23-18-22(13-14-24(23)28)25(29)19-26-15-7-1-2-8-16-30-17-9-6-12-21-10-4-3-5-11-21/h3-5,10-11,13-14,18,25-29H,1-2,6-9,12,15-17,19-20H2
2.1.3 InChI Key
GIIZNNXWQWCKIB-UHFFFAOYSA-N
2.1.4 Canonical SMILES
C1=CC=C(C=C1)CCCCOCCCCCCNCC(C2=CC(=C(C=C2)O)CO)O
2.2 Other Identifiers
2.2.1 UNII
2I4BC502BT
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Salmeterol Xinafoate

2. Serevent

3. Xinafoate, Salmeterol

2.3.2 Depositor-Supplied Synonyms

1. 89365-50-4

2. Serevent

3. Astmerole

4. Aeromax

5. Salmeterolum [latin]

6. 2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol

7. Gr 33343x

8. Salmaterol

9. Sn408d

10. 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol

11. Gr 33343 X

12. 2i4bc502bt

13. Chebi:64064

14. Gr-33343-x

15. Salmeterol Fluticasone Propionate Mixture

16. Salmeterolum

17. 4-(1-hydroxy-2-(6-(4-phenylbutoxy)hexylamino)ethyl)-2-(hydroxymethyl)phenol

18. 2-(hydroxymethyl)-4-[1-hydroxy-2-({6-[(4-phenylbutyl)oxy]hexyl}amino)ethyl]phenol

19. 4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)-2-(hydroxymethyl)phenol

20. Smr000466295

21. Hsdb 7315

22. Sr-01000076139

23. Salmeterol (usan/inn)

24. Unii-2i4bc502bt

25. Salmeterol [usan:inn:ban]

26. Ncgc00025247-01

27. Fluticasonepropiponate

28. (+-)-4-hydroxy-alpha'-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-m-xylene-alpha,alpha'-diol

29. (+-)-4-hydroxy-alpha1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-1,3-benzenedimethanol

30. Cpd000466295

31. Salmeterol [mi]

32. Salmeterol [inn]

33. Prestwick3_000945

34. Salmeterol Dimer Impurity

35. Salmeterol [hsdb]

36. Salmeterol [usan]

37. Dsstox_cid_3571

38. Salmeterol [vandf]

39. S 2692

40. Schembl4767

41. Chembl1263

42. Dsstox_rid_77087

43. Salmeterol [who-dd]

44. Dsstox_gsid_23571

45. Lopac0_001100

46. Bspbio_000910

47. Gtpl559

48. Mls000759000

49. Mls001424322

50. Salmeterol Related Compound H

51. Bpbio1_001002

52. Salmeterol Xinafoate Impurity 1

53. Dtxsid6023571

54. Bdbm25771

55. Hms2052h13

56. Hms2090e17

57. Hms2097n12

58. Hms3268k19

59. Hms3394h13

60. Hms3412p13

61. Hms3714n12

62. Hms3886g10

63. Amy37616

64. Bcp04199

65. Ex-a4409

66. Gr33343xgr33343x

67. Tox21_113584

68. Mfcd00867037

69. S5527

70. Stk629186

71. Akos005561914

72. Ccg-101194

73. Ccg-205176

74. Db00938

75. Nc00444

76. Sdccgsbi-0633788.p001

77. 1,3-benzenedimethanol, 4-hydroxy-.alpha.1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-

78. 1,3-benzenedimethanol, 4-hydroxy-alpha1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-, (+-)-

79. Mrf-0000468

80. Ncgc00015938-03

81. Ncgc00025247-02

82. 1,3-benzenedimethanol, 4-hydroxy-alpha(sup 1)-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-, (+-)-

83. 1,3-benzenedimethanol, 4-hydroxy-alpha(sup 1)-(((6-(4-phenylbutoxy)hexyl)amino)methyl-, (+-)-

84. As-56157

85. Hy-14302

86. Salmeterol 100 Microg/ml In Acetonitrile

87. Cas-89365-50-4

88. Ab00513972

89. Ft-0674508

90. Ft-0674509

91. C07241

92. C77008

93. D05792

94. Ab00513972-07

95. 365s504

96. En300-18530979

97. L000532

98. Q424333

99. Salmeterol Impurity H (xinafoate Adduct Impurity)

100. Q-101428

101. Sr-01000076139-2

102. Sr-01000076139-6

103. Brd-a01320529-001-05-9

104. 2-hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol

105. 5-[2-[6-(4-phenylbutoxy)hexylamino]-1-hydroxyethyl]-2-hydroxybenzenemethanol

106. ( Inverted Question Mark) 4-hydroxy-a1-[[[6-(4-phenylbutoxy)hexyl]amino]m-ethyl]-1,3-benzenedimethanol; Gr 33343x

107. 1-hydroxy-2-naphthoic Acid;4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]-2-methylol-phenol

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 415.6 g/mol
Molecular Formula C25H37NO4
XLogP33.9
Hydrogen Bond Donor Count4
Hydrogen Bond Acceptor Count5
Rotatable Bond Count16
Exact Mass g/mol
Monoisotopic Mass g/mol
Topological Polar Surface Area82
Heavy Atom Count30
Formal Charge0
Complexity403
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count1
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

Bronchodilator

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1497


Salmeterol ... /is/ indicated to prevent bronchospasm and reduce the frequency of acute asthma exacerbations in patients with chronic asthma who require regular treatment with an inhaled shorter-acting beta-adrenergic bronchodilator. ... Salmeterol may be used with or without concurrent inhaled or systemic corticosteroid therapy. During therapy with salmeterol ... , it is important for patients to have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks. /Included in US product labeling/

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 604


Salmeterol ... /is/ indicated for the prevention of exercise-induced bronchospasm. With use of salmeterol ... , it is important for patients to also have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks. ... /Included in US product labeling/

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 604


Salmeterol ... /is/ indicated as bronchodilators for the treatment of bronchospasm associated with chronic obstructive airway disease, including bronchitis and pulmonary emphysema. ... /Included in US product labeling/

Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 604


4.2 Drug Warning

Data from a large placebo-controlled safety study that was stopped early suggest that salmeterol may be associated with rare serious asthma episodes or asthma-related deaths. Data from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further suggest that the risk might be greater in African American patients. These results led to stopping the study prematurely. The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk. Given the similar basic mechanisms of action of beta2-agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect. Findings similar to the SMART study findings were reported in a prior 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence of asthma-related death was numerically, though not statistically, greater in patients with asthma treated with salmeterol (42 ug twice daily) versus albuterol (180 ug 4 times daily) added to usual asthma therapy.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004., p. 1617


Salmeterol oral inhalation therapy is intended for the maintenance treatment of asthma or chronic obstructive pulmonary disease (COPD) and should not be initiated in patients with substantially worsening or acutely deteriorating asthma or acute symptoms of COPD. ... Serious acute respiratory events, including fatalities, have been reported when salmeterol oral inhalation therapy has been initiated in such situations. In most cases, these adverse events have occurred in patients with severe asthma (e.g., those with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications, increasing need for inhaled short-acting beta-agonists, marked increase in symptoms, recent emergency room visits, sudden or progressive deterioration in pulmonary function). However, such events also have occurred in patients with less severe asthma. Although it has not been determined whether salmeterol oral inhalation therapy contributed to these events or simply failed to relieve the deteriorating asthma, the manufacturer states that use of salmeterol oral inhalation in patients with substantially worsening or acutely deteriorating asthma is inappropriate.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1313


Since salmeterol is cleared predominantly by hepatic metabolism, impaired liver function theoretically may lead to accumulation of the drug in plasma. Therefore, the manufacturer recommends that patients with hepatic disease be monitored closely while receiving salmeterol therapy.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1311


Usual doses of salmeterol oral inhalation generally produce no apparent cardiovascular effects. However, clinically important changes in systolic and/or diastolic blood pressure and heart rate, as well as ECG changes, have occurred infrequently with salmeterol therapy in controlled clinical studies. Adverse cardiovascular effects of salmeterol have in some instances required discontinuance of the drug. Hypertension has been reported with salmeterol inhalation aerosol or powder during postmarketing surveillance.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1311


For more Drug Warnings (Complete) data for SALMETEROL (21 total), please visit the HSDB record page.


4.3 Drug Indication

Salmeterol is indicated in the treatment of asthma with an inhaled corticosteroid, prevention of exercise induced bronchospasm, and the maintenance of airflow obstruction and prevention of exacerbations of chronic obstructive pulmonary disease.


FDA Label


5 Pharmacology and Biochemistry
5.1 MeSH Pharmacological Classification

Adrenergic beta-2 Receptor Agonists

Compounds bind to and activate ADRENERGIC BETA-2 RECEPTORS. (See all compounds classified as Adrenergic beta-2 Receptor Agonists.)


Bronchodilator Agents

Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)


5.2 ATC Code

R03AC12

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


R - Respiratory system

R03 - Drugs for obstructive airway diseases

R03A - Adrenergics, inhalants

R03AC - Selective beta-2-adrenoreceptor agonists

R03AC12 - Salmeterol


5.3 Absorption, Distribution and Excretion

Absorption

In asthmatic patients, a 50g dose of inhaled salmeterol powder reaches a Cmax of 47.897pg/mL, with a Tmax of 0.240h, and an AUC of 156.041pg/mL/h.


Route of Elimination

Salmeterol is 57.4% eliminated in the feces and 23% in the urine. Less than 5% of a dose is eliminated in the urine as unchanged salmeterol.


Volume of Distribution

In asthmatic patients, the volume of distribution of the central compartment is 177L and the volume of distribution of the peripheral compartment is 3160L.


Clearance

The average clearance of salmeterol in a group of asthmatic patients was 392L/h. Further data regarding the clearance of salmeterol is not readily available.


The absorption of salmeterol xinafoate from the respiratory tract following oral inhalation has not been fully characterized. Although it has been suggested that most of an orally inhaled drug actually is swallowed, the bronchodilating action of orally inhaled sympathomimetic agents is believed to result from a local action of the portion of the dose that reaches the bronchial tree. Systemic concentrations of salmeterol are low or undetectable after inhalation of the recommended dosage of the aerosol (42 ug) or powder (50 ug) twice daily and are not predictive of therapeutic effects.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1316


Binding of salmeterol averages 96% in vitro to human plasma proteins over the concentration range of 8-7722 ng/mL, which are concentrations greatly exceeding those achieved following usual doses of the drug. Salmeterol is bound to albumin and alpha 1 acid glycoprotein; the xinafoate moiety also is highly protein bound (greater than 99%) to albumin.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1317


The distribution of salmeterol into various human organs and tissues following oral inhalation has not been fully characterized. Results of studies in rats indicate that salmeterol crosses the blood-brain barrier in trace amounts.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1317


It is not known if salmeterol and/or its metabolites cross the placenta in humans. Following oral administration of 10 mg/kg of salmeterol in mice and rats, placental transfer of salmeterol occurred.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1317


For more Absorption, Distribution and Excretion (Complete) data for SALMETEROL (8 total), please visit the HSDB record page.


5.4 Metabolism/Metabolites

Salmeterol is predominantly metabolized by CYP3A4 to alpha-hydroxysalmeterol, and minorly by an unknown mechanism to an O-dealkylated metabolite.


... A minor metabolite is formed by o-dealkylation of the phenylalkyl side chain /of salmeterol/.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1317


... The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being alpha-hydroxysalmeterol, with subsequent elimination predominantly in the feces...

PMID:11825095 Cazzola M et al; Clin Pharmacokinet 41 (1): 19-30 (2002)


Hepatic, metabolized by hydroxylation via CYP3A4 Half Life: 5.5 hours


5.5 Biological Half-Life

The half life of salmeterol is 5.5h.


Following oral administration of salmeterol in healthy individuals, the terminal elimination half-lives of salmeterol and the xinafoate moiety are about 5.5 hours and 11-15 days, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 1317


5.6 Mechanism of Action

Beta-2 adrenoceptor stimulation causes relaxation of bronchial smooth muscle, bronchodilation, and increased airflow. Salmeterol is hypothesized to bind to 2 sites on the beta-2 adrenoceptor. The saligenin moiety binds to the active site of the beta-2 adrenoceptor. The hydrophilic tail of salmeterol binds to leucine residues in the exo-site of the beta-2 adrenoceptor almost irreversibly, allowing salmeterol to persist in the active site, which is responsible for it's long duration of action. Another hypothesis is that the lipophilic drug diffuses into lipid bilayer of smooth muscle cells and provides a depot of drug to the cells over a longer period of time.


In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol attenuate allergen-induced bronchial hyper-responsiveness.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004., p. 1615


The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, 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 cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004., p. 1615


Salmeterol is a long-acting beta-adrenergic agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta2-adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta1- and beta2-adrenoceptors. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these is not yet established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

Physicians Desk Reference. 58th ed. Thomson PDR. Montvale, NJ 2004., p. 1615


Salmeterol ... membrane binding is non-competitive and dissociation is slow so that its effects last for many hours. Despite this, salmeterol does not accumulate in tissues. Its mechanism of action can be explained by binding to a specific exo-site domain of the beta 2-receptor protein to produce continuous stimulation of the active site of the receptor, which gives salmeterol a profile of pharmacological activity unlike that of other beta 2-agonists. Due to its potent and prolonged activation of beta 2-adrenoceptors in airway smooth muscle cells, endothelial cells, mast cells and epithelial cells, salmeterol induces prolonged bronchodilatation, reduced vascular permeability, inhibition of inflammatory mediators, stimulation of ciliary function and modulation of ion and water transport across the bronchial mucosa.

PMID:8099695 Johnson M et al; Life Sci 52 (26): 2131-43 (1993)


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