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Chemistry

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Also known as: 107868-30-4, Aromasin, 6-methyleneandrosta-1,4-diene-3,17-dione, Fce 24304, Fce-24304, Exemestano
Molecular Formula
C20H24O2
Molecular Weight
296.4  g/mol
InChI Key
BFYIZQONLCFLEV-DAELLWKTSA-N
FDA UNII
NY22HMQ4BX

Exemestane
Exemestane is an irreversible steroidal aromatase inhibitor, with antiestrogen and antineoplastic activities. Upon oral administration, exemestane binds irreversibly to and inhibits the enzyme aromatase, thereby blocking the peripheral aromatization of androgens, including androstenedione and testosterone, to estrogens. This lowers estrogen levels in the blood circulation.
Exemestane is an Aromatase Inhibitor. The mechanism of action of exemestane is as an Aromatase Inhibitor.
1 2D Structure

Exemestane

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(8R,9S,10R,13S,14S)-10,13-dimethyl-6-methylidene-7,8,9,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,17-dione
2.1.2 InChI
InChI=1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1
2.1.3 InChI Key
BFYIZQONLCFLEV-DAELLWKTSA-N
2.1.4 Canonical SMILES
CC12CCC3C(C1CCC2=O)CC(=C)C4=CC(=O)C=CC34C
2.1.5 Isomeric SMILES
C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CC(=C)C4=CC(=O)C=C[C@]34C
2.2 Other Identifiers
2.2.1 UNII
NY22HMQ4BX
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 6-methyleneandrosta-1,4-diene-3,17-dione

2. Aromasil

3. Aromasin

4. Aromasine

5. Examestane

6. Fce 24304

7. Fce-24304

2.3.2 Depositor-Supplied Synonyms

1. 107868-30-4

2. Aromasin

3. 6-methyleneandrosta-1,4-diene-3,17-dione

4. Fce 24304

5. Fce-24304

6. Exemestano

7. Exemestanum

8. Exemestanum [inn-latin]

9. Exemestano [inn-spanish]

10. 6-methylene-androsta-1,4-diene-3,17-dione

11. Androsta-1,4-diene-3,17-dione, 6-methylene-

12. Fce24304

13. Pnu-155971

14. Aromasine

15. Ny22hmq4bx

16. Chebi:4953

17. (8r,9s,10r,13s,14s)-10,13-dimethyl-6-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-3h-cyclopenta[a]phenanthrene-3,17(6h)-dione

18. (8r,9s,10r,13s,14s)-10,13-dimethyl-6-methylene-7,8,9,11,12,13,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17(10h,14h)-dione

19. (8r,9s,10r,13s,14s)-10,13-dimethyl-6-methylidene-7,8,9,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-3,17-dione

20. Aromasil

21. Nsc713563

22. Nsc-758907

23. Exe

24. Dsstox_cid_3037

25. Dsstox_rid_76844

26. Dsstox_gsid_23037

27. 6-methylideneandrosta-1,4-diene-3,17-dione

28. Exemestane [usan:inn:ban]

29. Nikidess

30. (8alpha,10alpha,13alpha)-6-methylideneandrosta-1,4-diene-3,17-dione

31. Aromasin (tn)

32. Smr000466314

33. Cas-107868-30-4

34. Hsdb 7463

35. Curator_000009

36. Unii-ny22hmq4bx

37. Exemestane (jan/usp/inn)

38. Ccris 9351

39. Ncgc00095289-01

40. Exemestane [inn]

41. Exemestane; Aromasin

42. Exemestane, Aromasin

43. Pnu 155971

44. Exemestane [mi]

45. Exemestane [jan]

46. Exemestane [hsdb]

47. Exemestane [usan]

48. Exemestane [vandf]

49. Exemestane [mart.]

50. Schembl6215

51. Aromasin (pharmacia Upjohn)

52. Exemestane [usp-rs]

53. Exemestane [who-dd]

54. Exemestane(fce 24304)

55. Mls000759419

56. Mls001424062

57. Gtpl7073

58. 6-methylenandrosta-1,17-dione

59. Chembl1200374

60. Dtxsid5023037

61. Exemestane [orange Book]

62. Exemestane, >=98% (hplc)

63. Exemestane [ep Monograph]

64. Bcpp000235

65. Exemestane [usp Monograph]

66. Hms2051j04

67. Hms3713h12

68. Bcp23353

69. Zinc3973334

70. Tox21_111499

71. Bdbm50398447

72. Pnu155971

73. S1196

74. Akos015840113

75. Akos015895161

76. Tox21_111499_1

77. Ac-2171

78. Bcp9000676

79. Ccg-100995

80. Cs-1766

81. Db00990

82. Ks-5136

83. Nc00245

84. Nsc 758907

85. Nsc-713563

86. Ncgc00271596-03

87. 6-methylenandrost-1,4-dien-3,17-dione

88. As-31053

89. Cpd000466314

90. Hy-13632

91. Bcp0726000226

92. 6-methylen-androst-1,4-diene-3,17-dione

93. E0941

94. C08162

95. D00963

96. Ab00639936-06

97. Ab00639936-08

98. Ab00639936-09

99. Ab00639936-10

100. Ab00639936_11

101. 868e304

102. A801772

103. Q418819

104. Sr-01000759393

105. Sr-01000759393-4

106. Brd-k33425534-001-12-5

107. Exemestane, European Pharmacopoeia (ep) Reference Standard

108. Exemestane, United States Pharmacopeia (usp) Reference Standard

109. Exemestane, Pharmaceutical Secondary Standard; Certified Reference Material

110. Exemestane For System Suitability, European Pharmacopoeia (ep) Reference Standard

111. (1s,2r,10r,11s,15s)-2,15-dimethyl-8-methylidenetetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-3,6-diene-5,14-dione

112. Exm

2.4 Create Date
2005-03-26
3 Chemical and Physical Properties
Molecular Weight 296.4 g/mol
Molecular Formula C20H24O2
XLogP33.1
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count2
Rotatable Bond Count0
Exact Mass296.177630004 g/mol
Monoisotopic Mass296.177630004 g/mol
Topological Polar Surface Area34.1 Ų
Heavy Atom Count22
Formal Charge0
Complexity653
Isotope Atom Count0
Defined Atom Stereocenter Count5
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 4  
Drug NameAromasin
PubMed HealthExemestane (By mouth)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent
Drug LabelAROMASIN Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structu...
Active IngredientExemestane
Dosage FormTablet
RouteOral
Strength25mg
Market StatusPrescription
CompanyPharmacia And Upjohn

2 of 4  
Drug NameExemestane
PubMed HealthExemestane (By mouth)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent
Drug LabelEXEMESTANE tablets for oral administration contain 25 mg of EXEMESTANE, an irreversible, steroidal aromatase inactivator. EXEMESTANE is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structu...
Active IngredientExemestane
Dosage FormTablet
RouteOral
Strength25mg
Market StatusPrescription
CompanyAlvogen; Roxane

3 of 4  
Drug NameAromasin
PubMed HealthExemestane (By mouth)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent
Drug LabelAROMASIN Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structu...
Active IngredientExemestane
Dosage FormTablet
RouteOral
Strength25mg
Market StatusPrescription
CompanyPharmacia And Upjohn

4 of 4  
Drug NameExemestane
PubMed HealthExemestane (By mouth)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent
Drug LabelEXEMESTANE tablets for oral administration contain 25 mg of EXEMESTANE, an irreversible, steroidal aromatase inactivator. EXEMESTANE is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structu...
Active IngredientExemestane
Dosage FormTablet
RouteOral
Strength25mg
Market StatusPrescription
CompanyAlvogen; Roxane

4.2 Therapeutic Uses

Antineoplastic (hormonal).

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. 692


Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1434


Use of exemestane in premenopausal women is not accepted. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1434


4.3 Drug Warning

Adverse events of any cause observed in the overall clinical trials program (N=1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%) and fever (5%). Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2602


Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving /exemestane/ 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2601


Other adverse effects occurring in at least 5%, regardless of causality, include mental depression, pain, insomnia, anxiety, dyspnea, dizziness, headache, edema, vomiting, abdominal pain, anorexia, cough, flu-like symptoms, hypertension, and constipation.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 1044


Lymphocytopenia grade 3 or 4 was also reported in 20% of patients; however, 89% of these patients had a preexisting lower-grade lymphopenia, and 40% either recovered or improved to a lesser severity lymphopenia during exemestane. Patients did not experience a significant increase in viral infections, and no opportunistic infections were observed.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 1044


For more Drug Warnings (Complete) data for EXEMESTANE (11 total), please visit the HSDB record page.


4.4 Drug Indication

For the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands. The aromatase inhibitors (AIs) are drugs that reduce estrogen levels by blocking the action of aromatase in the adrenal glands. The selective AIs (SAIs) selectively reduce levels of estrogen without interfering with levels of other steroid hormones that are produced by the adrenal gland. Drugs in this class include anastrozole (Arimidex ™), letrozole (Femara ™) and exemestane (Aromasin ™).


5.2 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)


Aromatase Inhibitors

Compounds that inhibit AROMATASE in order to reduce production of estrogenic steroid hormones. (See all compounds classified as Aromatase Inhibitors.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
EXEMESTANE
5.3.2 FDA UNII
NY22HMQ4BX
5.3.3 Pharmacological Classes
Aromatase Inhibitors [MoA]; Aromatase Inhibitor [EPC]
5.4 ATC Code

L - Antineoplastic and immunomodulating agents

L02 - Endocrine therapy

L02B - Hormone antagonists and related agents

L02BG - Aromatase inhibitors

L02BG06 - Exemestane


5.5 Absorption, Distribution and Excretion

Absorption

42%


Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 nghr/mL) were about twice those in healthy women (41.4 nghr/mL).

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and (alpha) 1 -acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


For more Absorption, Distribution and Excretion (Complete) data for EXEMESTANE (11 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

Hepatic


Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


5.7 Biological Half-Life

24 hours


Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2600


... The terminal half-life was 8.9 hr. Maximal estradiol suppression of 62 +/- 14% was observed at 12 hr.

PMID:14671195 Mauras N et al; J Clin Endocrinol Metab 88 (12): 5951-6 (2003)


5.8 Mechanism of Action

Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It irreversibly binds to the active site causing permanent inhibition necessitating de novo synthesis to restore enzymatic function. Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on the adrenal biosynthesis of corticosteroids or aldosterone. This reduction in serum and tumor concentrations of estrogen delays tumor growth and disease progression. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.


... exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors...

PMID:14671195 Mauras N et al; J Clin Endocrinol Metab 88 (12): 5951-6 (2003)


Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Physicians Desk R