Nestorone

Nestorone (NES) is a synthetic progestogen designed with high specificity for the progesterone receptor. It is being investigated for use in hormonal contraceptives but is currently not used in any approved products internationally.

Tags
nestorone
MOL SDF CML

Identifiers

Abbreviation

NES

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References

Names

  • Nestoron
  • segesterone acetate
  • elcometrine
  • ST1435
  • ST-1435
  • 16-methylene-17α-acetoxy-19-nor-4-pregnene-3,20-dione acetate
  • 17-hydroxy-16-methylene-19-norpregn-4-ene-3,20-dione acetate

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References

  1. ID = 108059. Nestorone. (View all citations for this reference)

CASRN

7759-35-5

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References

PubChem CID

108059

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References

  1. ID = 108059. Nestorone. (View all citations for this reference)

UNII

9AMX4Q13CC

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References

  1. UNII: Segesterone Acetate (View all citations for this reference)

Wikipedia Entry Name

Segesterone Acetate

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References

  1. Wikipedia: Segesterone Acetate (View all citations for this reference)

ChEBI ID

CHEBI:135563

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References

  1. ChEBI: Elcometrine (View all citations for this reference)

ChEMBL ID

CHEMBL3707377

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References

  1. ChEMBL: Segesterone Acetate (View all citations for this reference)

ChemSpider ID

97161

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References

  1. ChemSpider: Segesterone Acetate (View all citations for this reference)

Physical & Chemical Properties

Molecular Formula

C23H30O4

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References

Molecular Weight

370.482 g/mol

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References

Melting Point

178-179° C

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References

  1. Reaxys: Nestorone, ID 3122987. (View all citations for this reference)

Solubility

Soluble in DMSO, 5 mg/mL

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References

  1. Nestorone. Sigma-Aldrich SML0550. (View all citations for this reference)

Specific Optical Rotation

-103.3 °, 1g/100 mL CHCl3

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References

  1. Reaxys: Nestorone, ID 3122987. (View all citations for this reference)

Toxicology

Genotoxicity

3 tests showed no gene mutations and did not affect chromosomal integrity

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References

  1. Jordan A. Toxicology of progestogens of implantable contraceptives for women. Contraception. 2002; 65:3-8.
    2. (View all citations for this reference)

Safety Profile Overview

Similar safety profile to progestogens found in approved oral contraceptives; no significant or unusual toxicities.

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References

  1. Jordan A. Toxicology of progestogens of implantable contraceptives for women. Contraception. 2002; 65:3-8.
    2. (View all citations for this reference)

Biochemistry & Pharmacology

Progesterone Receptor Activity

Agonist

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References

  1. Kumar, N.; Fagart, J.; Liere, P.; Mitchell, S. J.; Knibb, A. R.; Petit-Topin, I.; Rame, M.; El-Etr, M.; Schumacher, M.; Lambert, J. J.; Rafestin-Oblin, M. E.; Sitruk-Ware, R., Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 2017, 158 (1), 170-182.
    2. (View all citations for this reference)

Androgen Receptor Activity

No activity

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
    2. (View all citations for this reference)
  2. Kumar, N.; Fagart, J.; Liere, P.; Mitchell, S. J.; Knibb, A. R.; Petit-Topin, I.; Rame, M.; El-Etr, M.; Schumacher, M.; Lambert, J. J.; Rafestin-Oblin, M. E.; Sitruk-Ware, R., Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 2017, 158 (1), 170-182.
    3. (View all citations for this reference)
  3. Kumar, N.; Koide, S. S.; Tsong, Y.; Sundaram, K., Nestorone: a progestin with a unique pharmacological profile. Steroids 2000, 65 (10-11), 629-36.
    4. (View all citations for this reference)
  4. Sitruk-Ware, R.; Small, M.; Kumar, N.; Tsong, Y.-Y.; Sundaram, K.; Jackanicz, T., Nestorone®: clinical applications for contraception and HRT. Steroids 2003, 68 (10-13), 907-913.
    5. (View all citations for this reference)
  5. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    6. (View all citations for this reference)
  6. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    7. (View all citations for this reference)
  7. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    8. (View all citations for this reference)

Estrogen Receptor Activity

Antagonist

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References

  1. Kumar, N.; Fagart, J.; Liere, P.; Mitchell, S. J.; Knibb, A. R.; Petit-Topin, I.; Rame, M.; El-Etr, M.; Schumacher, M.; Lambert, J. J.; Rafestin-Oblin, M. E.; Sitruk-Ware, R., Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology 2017, 158 (1), 170-182.
    2. (View all citations for this reference)
  2. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    3. (View all citations for this reference)
  3. Sitruk-Ware, R.; Small, M.; Kumar, N.; Tsong, Y.-Y.; Sundaram, K.; Jackanicz, T., Nestorone®: clinical applications for contraception and HRT. Steroids 2003, 68 (10-13), 907-913.
    4. (View all citations for this reference)
  4. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    5. (View all citations for this reference)
  5. Kumar, N.; Koide, S. S.; Tsong, Y.; Sundaram, K., Nestorone: a progestin with a unique pharmacological profile. Steroids 2000, 65 (10-11), 629-36.
    6. (View all citations for this reference)

Glucocorticoid Receptor Activity

Binds to GR but does not show activity in in vivo assays

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References

  1. Sitruk-Ware, R., Pharmacological profile of progestins. Maturitas 2004, 47, 277-283.
    2. (View all citations for this reference)
  2. Kumar, N.; Koide, S. S.; Tsong, Y.; Sundaram, K., Nestorone: a progestin with a unique pharmacological profile. Steroids 2000, 65 (10-11), 629-36.
    3. (View all citations for this reference)
  3. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    4. (View all citations for this reference)
  4. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    5. (View all citations for this reference)
  5. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    6. (View all citations for this reference)

Mineralocorticoid Receptor Activity

No activity

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References

  1. Hapgood, J. P.; Africander, D.; Louw, R.; Ray, R. M.; Rohwer, J. M., Potency of progestogens used in hormonal therapy: toward understanding differential actions. J Steroid Biochem Mol Biol 2013, 142, 39-47.
    2. (View all citations for this reference)
  2. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    3. (View all citations for this reference)

Elimination Half-Life (t1/2)

26.8 h

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References

  1. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    2. (View all citations for this reference)

Serum Protein Binding

Binds to albumin. Does not bind to SHBG.

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References

  1. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    2. (View all citations for this reference)
  2. Thomas L. Lemke; David A. Williams; Victoria F. Roche; S. William Zito (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 1403. ISBN 978-1-60913-345-0.
    3. (View all citations for this reference)
  3. Kumar, N.; Koide, S. S.; Tsong, Y.; Sundaram, K., Nestorone: a progestin with a unique pharmacological profile. Steroids 2000, 65 (10-11), 629-36.
    4. (View all citations for this reference)
  4. Sitruk-Ware, R.; Small, M.; Kumar, N.; Tsong, Y.-Y.; Sundaram, K.; Jackanicz, T., Nestorone®: clinical applications for contraception and HRT. Steroids 2003, 68 (10-13), 907-913.
    5. (View all citations for this reference)

Enzyme Interactions

Inhibits 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and reduces the biosynthesis of several endogenous steroids.

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References

  1. Toit, R. L. D.; Perkins, M. S.; Snoep, J. L.; Storbeck, K. H.; Africander, D., Fourth-generation progestins inhibit 3β-hydroxysteroid dehydrogenase type 2 and modulate the biosynthesis of endogenous steroids. PLoS ONE 2016, 11, 1-24.
    2. (View all citations for this reference)

Route of Administration

Parenteral. Orally inactive.

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References

  1. Su, Y.; Lian, Q. Q.; Ge, R. S., Contraceptives with novel benefits. Expert Opin Investig Drugs 2012, 21 (1), 83-90.
    2. (View all citations for this reference)

Metabolites

Name
Structure
Notes
Segesterone (17α-deacetylnestorone)
structure

Minor metabolite. Also a degradant (see Nestorone Impurity 13). HPLC and MS.

4,5-dihydro-17α-deacetylnestorone
structure

Major metabolite as identified by Prasad et al. (19 total metabolites found but only 2 identified). HPLC and MS.

3β,5α-tetrahydronestorone
structure

Most abundant metabolite in mouse plasma at 1 h post administration.

3α,5α-tetrahydronestorone
structure

120 times less potent PR activity than Nestorone in human PR (hPR) transactivation assay (EC50 = 24 pM for NES vs. 2850 pM for metabolite). GC/MS-MS.

5α-dihydronestorone
structure

Identified in vitro, detected in plasma and brain of mice. Most abundant metabolite in mouse brain at 30 min post administration. 17 times less potent PR activity than nestorone in human PR transactivation assay (EC50 = 410 pM vs. EC50 of Nestorone = 24 pM).

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Impurities

Name
Structure
CASRN
Other Names & Identifiers
Segesterone
structure

7690-08-6

  • 16-methylene-17α-hydroxy-19-nor-pregn-4-ene-3,20-dione
  • 17α-hydroxy-16-methylene-19-norprogesterone
  • 17α-deacetylnestorone

4,5-Dihydronestorone
structure

1052717-88-0

5(10)-Ene-3-one Nestorone Derivative
structure

1-Ene-3-one Nestorone Derivative
structure

3-Deoxonestorone
structure

View All (13)