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Lasofoxifene

Lasofoxifene

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Also known as: 180916-16-9, Rac-lasofoxifene, Oporia, Cp 336156, 180915-78-0, (5r,6s)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

Molecular Formula

C₂₈H₃₁NO₂

Molecular Weight

413.5 g/mol

InChI Key

GXESHMAMLJKROZ-IAPPQJPRSA-N

FDA UNII

337G83N988

Lasofoxifene is a non-steroidal, naphthalene-derived, third-generation selective estrogen receptor modulator (SERM) with potential antineoplastic and anti-osteoporotic activities. Upon oral administration, lasofoxifene selectively binds to both estrogen receptor alpha (ERalpha; ESR1) and estrogen receptor beta (ERbeta; ESR2) with high affinity and mimics the effects of endogenous estradiol with varying agonist and antagonist effects in ER-expressing tissues. Blockade of ERalpha by lasofoxifene may potentially inhibit estrogen-dependent cancer cell proliferation in ER-expressing cancers. Lasofoxifene may also bind to the certain mutant forms of ERalpha, including the Y537S ESR1 mutant, making it potentially useful in the treatment of tumors that have acquired resistance to other ER-targeting agents.

1 2D Structure

Lasofoxifene

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

2.1.2 InChI

InChI=1S/C28H31NO2/c30-24-11-15-27-23(20-24)10-14-26(21-6-2-1-3-7-21)28(27)22-8-12-25(13-9-22)31-19-18-29-16-4-5-17-29/h1-3,6-9,11-13,15,20,26,28,30H,4-5,10,14,16-19H2/t26-,28+/m1/s1

2.1.3 InChI Key

GXESHMAMLJKROZ-IAPPQJPRSA-N

2.1.4 Canonical SMILES

C1CCN(C1)CCOC2=CC=C(C=C2)C3C(CCC4=C3C=CC(=C4)O)C5=CC=CC=C5

2.1.5 Isomeric SMILES

C1CCN(C1)CCOC2=CC=C(C=C2)[C@H]3[C@H](CCC4=C3C=CC(=C4)O)C5=CC=CC=C5

2.2 Other Identifiers

2.2.1 UNII

337G83N988

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (-)-cis-5,6,7,8-tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol

2. Cis-1r-(4'-pyrrolidinoethoxyphenyl)-2s-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene, Tartrate Salt

3. Cp 336156

4. Cp-336,156

5. Las Estrogen Receptor Modulator

6. Lasofoxifene Hydrochloride

2.3.2 Depositor-Supplied Synonyms

1. 180916-16-9

2. Rac-lasofoxifene

3. Oporia

4. Cp 336156

5. 180915-78-0

6. (5r,6s)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

7. Cp-336,156

8. (-)-cis-5,6,7,8-tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol

9. Chembl328190

10. 337g83n988

11. Rel-(5r,6s)-6-phenyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

12. Lasofoxifene [inn]

13. (5r,6s)-6-phenyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

14. (5r,6s)-6-phenyl-5-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,6,7,8-tetrahydronaphthalen-2-ol

15. (5r,6s)-6-phenyl-5-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol.

16. 2-naphthalenol, 5,6,7,8-tetrahydro-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-, (5r,6s)-

17. Lasofoxifene [inn:ban]

18. Lasofoxifene Hcl

19. Cp-336156

20. Lasofoxifeno

21. Lasofoxifenum

22. Unii-337g83n988

23. 2-naphthalenol, 5,6,7,8-tetrahydro-6-phenyl-5-(4-(2-(1-pyrrolidinyl)ethoxy)phenyl)-, (5r,6s)-

24. C3d

25. Lasofoxifene [mi]

26. (5r,6s)-5,6,7,8-tetrahydro-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-2-naphthalenol

27. Schembl26815

28. Lasofoxifene [mart.]

29. Lasofoxifene [who-dd]

30. Gtpl7542

31. Lasofoxifene [ema Epar]

32. Bdbm20606

33. Dtxsid50171037

34. Chebi:135938

35. Bcp03626

36. Hy-a0037

37. Zinc3918428

38. Akos030241621

39. Bcp9000842

40. Db06202

41. Ncgc00487269-02

42. Bcp0726000177

43. Cs-0006740

44. 916l169

45. Q644675

46. J-011550

47. (-)-cis-5,6,7,8-tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol.

48. Cis-6-phenvl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol

49. Cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

50. Cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol

51. Cis-6phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol

52. (-)-cis-(5r,6s)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

53. 2-naphthalenol, 5,6,7,8-tetrahydro-6-phenyl-5-(4-(2-(1-pyrrolidinyl)ethoxy)phenyl)-, (5r-cis)-

2.4 Create Date

2005-08-09

3 Chemical and Physical Properties

Molecular Formula	C₂₈H₃₁NO₂
Molecular Weight	413.5 g/mol
XLogP3	6.1
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	3
Rotatable Bond Count	6
Exact Mass	413.235479232 g/mol
Monoisotopic Mass	413.235479232 g/mol
Topological Polar Surface Area	32.7 Å²
Heavy Atom Count	31
Formal Charge	0
Complexity	533
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Investigated for use/treatment in postmenopausal osteoporosis to reduce the risk of both vertebral and novertebral fractures, as well as address other postmenopausal conditions, including reduction in risk of breast cancer and treatment of vulvar and vaginal atrophy (VVA)

Fablyn is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. A significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated (see section 5. 1).

When determining the choice of Fablyn or other therapies, including oestrogens, for a postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5. 1).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Lasofoxifene exhibits both significant estrogenic and antiestrogenic activity both in vitro and in vivo, targeting any tissues that possess ERs, such as bone, uterus, breast, blood vessels, and liver. Binding assays demonstrated high affinity of the compound for both ER and ER in a tissue-dependent manner. It mimics the effects of estradiol with varying agonist and antagonist effects.

5.2 ATC Code

G03

G - Genito urinary system and sex hormones

G03 - Sex hormones and modulators of the genital system

G03X - Other sex hormones and modulators of the genital system

G03XC - Selective estrogen receptor modulators

G03XC03 - Lasofoxifene

5.3 Absorption, Distribution and Excretion

Absorption

Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours. Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure. In a comparative study in the rat, lasofoxifene showed bioavailability of 62%.

Route of Elimination

Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug.

Volume of Distribution

The apparent volume of distribution in postmenopausal women is 1350L.

Clearance

The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr.

5.4 Metabolism/Metabolites

Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols.

Lasofoxifene has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[[(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]oxane-2-carboxylic acid.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.5 Biological Half-Life

Elimination half-life is approximately 6 days.

5.6 Mechanism of Action

Lasofoxifene mediates an agonist effect on estrogen receptors expressed on bone to mimic the positive effects of estrogen to reduce the production and lifespan of osteoclasts via altering the NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, stimulation of osteoblast (the bone forming cells) activity and additional effects on calcium homeostasis. It acts as an antagonist at uterus and mammary glands by suppressing the estrogen signaling in oncogenic pathways and inhibits the downstream gene transcription. A study also suggests that lasofoxifene may also act as an inverse agonist at CB2 cannabinoid receptor which is expressed in bone to inhibit osteoclast formation and resorptive activity.