Norgestimate

Norgestimate is a synthetic progestogen used in combined oral contraceptives and hormone replacement therapy. It is a prodrug of norelgestromin, and, to a much lesser extent, levonorgestrel.

Tags
Approvals
US FDA-Approved
Related Compounds
Norelgestromin Levonorgestrel
norgestimate
MOL SDF CML

Identifiers

Abbreviation

NGM

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References

  1. Wong, F. A.; Edom, R. W.; Duda, M.; Tischio, J. P.; Huang, M.; Juzwin, S.; Tegegne, G. Determination of Norgestimate and Its Metabolites in Human Serum Using High-Performance Liquid Chromatography with Tandem Mass Spectrometric Detection. J. Chromatogr. B Biomed. Sci. Appl. 1999, 734 (2), 247–256. (View all citations for this reference)

Names

  • (3EZ)-13β-ethyl-3-(hydroxyimino)-18,19-dinor-17α-pregn-4-en-20-yn-17-yl acetate
  • ORF-10131
  • Norgestrel acetate oxime

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References

CASRN

35189-28-7

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References

PubChem CID

6540478

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References

  1. PubChem: Norgestimate (View all citations for this reference)

IUPHAR/BPS

7091

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References

  1. IUPHAR/BPS: Norgestimate (View all citations for this reference)

DrugBank Accession Number

DB00957

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References

  1. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

UNII

C291HFX4DY

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References

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

KEGG Entry Number

D05209

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References

  1. KEGG: Norgestimate (View all citations for this reference)

Wikipedia Entry Name

Norgestimate

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References

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

ChEBI ID

CHEBI:50815

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References

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

ChEMBL ID

CHEMBL1200934

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References

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

ATC Code(s)

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References

  1. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Physical & Chemical Properties

Molecular Formula

C23H31NO3

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References

Molecular Weight

369.497 g/mol

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References

Appearance

White or almost white powder

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References

  1. British Pharmacopoeia 2017: Norgestimate monograph
    2. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

Melting Point

216° C
IARC, Toxnet: 214-218 °C

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References

  1. ChemIDPlus: A Toxnet Database. Norgestimate. (View all citations for this reference)
  2. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  3. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  4. Toxnet: Norgestimate. (View all citations for this reference)

Solubility

Practically insoluble in water, freely soluble in methylene chloride, soluble in acetone, sparingly soluble in acetonitrile.

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References

  1. British Pharmacopoeia 2017: Norgestimate monograph
    2. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

logP

4.8

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References

  1. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Specific Optical Rotation

USP, IARC: +40° to +46°, 10 mg/mL in chloroform
BP: +42° to +50°, 0.200 g in 20.0 mL methylene chloride
Toxnet: +110 ° at 25 °C in unspecified solvent

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References

  1. USP 40: Norgestimate monograph.
    2. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  3. Toxnet: Norgestimate. (View all citations for this reference)

Storage Conditions

Store at 25 °C, do no go outside of range 15-30 °C.

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References

  1. Toxnet: Norgestimate. (View all citations for this reference)

Ratio of (E)- to (Z)- Isomer

1.27 to 1.78

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References

  1. British Pharmacopoeia 2017: Norgestimate monograph
    2. (View all citations for this reference)

Biochemistry & Pharmacology

Progesterone Receptor Activity

Partial agonist

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References

  1. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  2. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  3. Paris, F.; Balaguer, P.; Rimbault, F.; Gaspari, L.; Sultan, C. Molecular Action of Norgestimate: New Developments. Gynecol. Endocrinol. 2015, 31 (6), 487–490. (View all citations for this reference)

Androgen Receptor Activity

Reports vary: "minimal androgenic activity" (Phillips), agonist (Ruan, Lello), partial agonist (DrugBank).

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References

  1. Phillips A, Hahn DW, McGuire JL (1992). "Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity". Am. J. Obstet. Gynecol. 167 (4 Pt 2): 1191–6. (View all citations for this reference)
  2. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    3. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    4. (View all citations for this reference)

Estrogen Receptor Activity

Antagonist (Ruan, Lello). Selective agonist for ERα (Paris).

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References

  1. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    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)
  3. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  4. Paris, F.; Balaguer, P.; Rimbault, F.; Gaspari, L.; Sultan, C. Molecular Action of Norgestimate: New Developments. Gynecol. Endocrinol. 2015, 31 (6), 487–490. (View all citations for this reference)

Glucocorticoid Receptor Activity

Pronounced as "unknown" by Stanczyk in 2013, but previously claimed as not active (Ruan, Lello). Recently (2015) defined as full antagonist with low affinity (Paris).

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)
  2. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    3. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    4. (View all citations for this reference)
  4. Paris, F.; Balaguer, P.; Rimbault, F.; Gaspari, L.; Sultan, C. Molecular Action of Norgestimate: New Developments. Gynecol. Endocrinol. 2015, 31 (6), 487–490. (View all citations for this reference)

Mineralocorticoid Receptor Activity

Varies: Full antagonist with moderate activity (Paris). No activity (Ruan, Lello).

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References

  1. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    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)
  3. Paris, F.; Balaguer, P.; Rimbault, F.; Gaspari, L.; Sultan, C. Molecular Action of Norgestimate: New Developments. Gynecol. Endocrinol. 2015, 31 (6), 487–490. (View all citations for this reference)

Target Pathways

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References

  1. KEGG: Norgestimate (View all citations for this reference)

Serum Protein Binding

Metabolites bind at >97%. Norelgestromin binds to albumin and not SHBG, while norgestrel binds primarily to SHBG.

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References

  1. Toxnet: Norgestimate. (View all citations for this reference)

Metabolism

Hepatic, CYP3A4

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References

  1. Toxnet: Norgestimate. (View all citations for this reference)
  2. Nanda, K.; Stuart, G. S.; Robinson, J.; Gray, A. L.; Tepper, N. K.; Gaffield, M. E. Drug Interactions between Hormonal Contraceptives and Antiretrovirals. AIDS 2017, 31 (7), 917–952. (View all citations for this reference)

Excretion

Metabolites excreted via fecal and renal pathways.

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References

  1. Toxnet: Norgestimate. (View all citations for this reference)

Inhibition of Ovulation

0.25 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Transformation of Endometrium

5-10 mg/cycle

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Menstrual Delay

5 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    2. (View all citations for this reference)

Indications

Dysfunctional uterine bleeding, dysmenorrhea, hirsutism, hypermenorrhea, postmenopausal osteoporosis, moderate acne vulgaris, moderate & severe vulvovaginal atrophy, moderate & severe vasomotor symptoms

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References

  1. DrugBank: Norgestimate
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Metabolites

Name
Structure
Notes
18,19-Dinor-17-pregn-4-ene-20-yn-3-one, 17-hydroxy-13-ethyl, (17α)-(-)
structure

18,19-dinor-5β-17-pregnan-20-yn, 3α,17β-dihydroxy-13-ethyl, 17α
structure

Minor metabolite.

Other Norgestimate Metabolites

Other metabolites include various hydroxylated and conjugated species.

Levonorgestrel Acetate
structure

Very minor metabolite. Also known as 3-keto norgestimate.

Levonorgestrel
structure

An active metabolite of norelgestromin and a secondary metabolite of norgestimate.

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Impurities

Name
Structure
CASRN
Other Names & Identifiers
(E)-Norelgestromin
structure

  • BP Norgestimate Impurity C
  • (3E)-13β-ethyl-3-(hydroxyimino)-18,19-dinor-17α-pregn-4-en-20-yn-17-ol

Levonorgestrel
structure

797-63-7

  • BP Norgestimate Impurity B

(Z)-Norelgestromin
structure

  • BP Norgestimate Impurity D
  • (3Z)-13β-ethyl-3-(hydroxyimino)-18,19-dinor-17α-pregn-4-en-20-yn-17-ol

Levonorgestrel Acetate
structure

  • BP Norgestimate Impurity A
  • 13β-ethyl-3-oxo-18,19-dinor-17α-pregn-4-en-20-yn-17-yl acetate

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US FDA-Approved Products

Name
Formulation
Status
ANDA #
Prefest
ESTRADIOL: 1 mg, 1 mg NORGESTIMATE: N/A, 0.09 mg Oral tablet

Discontinued

021040

Estradiol and Norgestimate
ESTRADIOL: 1 mg, 1 mg NORGESTIMATE: N/A, 0.09 mg Oral tablet

Prescription

076812

Tri-Sprintec
ETHINYL ESTRADIOL: 0.035 mg, 0.035 mg, 0.035 mg NORGESTIMATE: 0.18 mg, 0.215 mg, 0.25 mg 28 oral tablets

Prescription

075808

Tri-Previfem
ETHINYL ESTRADIOL: 0.035 mg, 0.035 mg, 0.035 mg NORGESTIMATE: 0.18 mg, 0.0215 mg, 0.25 mg 28 oral tablets

Prescription

076335

Tri-Mili
ETHINYL ESTRADIOL: 0.035 mg, 0.035 mg, 0.035 mg NORGESTIMATE: 0.18 mg, 0.215 mg, 0.25 mg 28 oral tablets

Prescription

205441

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