19-Norprogesterone

Last updated
19-Norprogesterone
19-Norprogesterone.svg
Clinical data
Other names10-Norprogesterone; 19-Norpregn-4-ene-3,20-dione; 17β-Acetylestr-4-en-3-one
Routes of
administration 		Parenteral
Drug class Progestin; Progestogen; Mineralocorticoid
Identifiers
  • (8R,9S,10R,13S,14S,17S)-17-acetyl-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H28O2
Molar mass 300.442 g·mol−1
3D model (JSmol)
Melting point 144 to 145 °C (291 to 293 °F)
  • O=C4\C=C2/[C@@H]([C@H]1CC[C@@]3([C@@H](C(=O)C)CC[C@H]3[C@@H]1CC2)C)CC4
  • InChI=1S/C20H28O2/c1-12(21)18-7-8-19-17-5-3-13-11-14(22)4-6-15(13)16(17)9-10-20(18,19)2/h11,15-19H,3-10H2,1-2H3/t15-,16+,17+,18+,19-,20+/m0/s1
  • Key:NVUUMOOKVFONOM-GPBSYSOESA-N

19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a steroidal progestin and close analogue of the sex hormone progesterone, lacking only the C19 methyl group of that molecule. It was first synthesized in 1944 in the form of a mixture that also included unnatural stereoisomers (probably C14 (β) and C17 (α)) of progesterone, and this mixture was found to be at least equivalent to progesterone in terms of progestogenic activity. [1] [2] [3] [4] Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. [3] [4] 19-Norprogesterone was resynthesized in 1951 with an improved method, [3] and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. [3] In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the Clauberg assay in rabbits, [5] and at the time of this discovery, 19-norprogesterone was the most potent progestogen known. [6] [7]

Contents

Similarly to progesterone, 19-norprogesterone is a potent progestogen and possesses high affinity for the mineralocorticoid receptor (MR). [8] However, unlike progesterone, which is an antagonist of the MR, 19-norprogesterone acts as a partial agonist of the MR and produces mineralocorticoid effects such as sodium retention, polydipsia, and hypertension in animals. [8] Like progesterone, 19-norprogesterone is very active as a progestogen parenterally but is only minimally active orally. [8] A SAR Tooltip structure-activity relationship study found that 19-norprogesterone had 47% of the affinity of aldosterone for the rat MR and that 17α-hydroxylation (17α-hydroxy-19-norprogesterone, or gestronol) decreased it to 13%. [8] The addition of 6-methylation with formation of a double bond at this position (nomegestrol) further decreased the MR affinity to 1.2% of that of aldosterone, and subsequent acetylation of the 17α-hydroxy group (nomegestrol acetate) nearly abolished it (0.23%). [8]

The discovery of the retained and potentiated progestogenic activity of 19-norsteroids like 19-norprogesterone resulted in the synthesis of norethisterone, and in turn, the introduction of the first hormonal contraceptives. [6] [7] It was reasoned that since ethisterone (17α-ethinyltestosterone) is orally active, and since 19-norprogesterone is a very potent progestin parenterally, that 17α-ethynyl-19-nortestosterone (known now as norethisterone or norethindrone) might be a potent, orally active progestin, and indeed, this was found to be the case. [6]

Chemistry

Derivatives

19-Norprogesterone is the parent compound of a group of medically used progestins, which includes the following: [9] [10] [11]

In addition, the testosterone analogue of 19-norprogesterone, 19-nortestosterone (also known as nandrolone), is an anabolic-androgenic steroid (AAS) and progestogen, and is the parent compound of a large group of AAS and progestins that includes norethisterone.

See also

Related Research Articles

<span class="mw-page-title-main">Progestogen</span> Steroid hormone that activates the progesterone receptor

Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. The progestogens are named for their function in maintaining pregnancy, although they are also present at other phases of the estrous and menstrual cycles.

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestonorone caproate</span> Chemical compound

Gestonorone caproate, also known as gestronol hexanoate or norhydroxyprogesterone caproate and sold under the brand names Depostat and Primostat, is a progestin medication which is used in the treatment of enlarged prostate and cancer of the endometrium. It is given by injection into muscle typically once a week.

<span class="mw-page-title-main">Promegestone</span> Chemical compound

Promegestone, sold under the brand name Surgestone, is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders. It is taken by mouth.

<span class="mw-page-title-main">Demegestone</span> Chemical compound

Demegestone, sold under the brand name Lutionex, is a progestin medication which was previously used to treat luteal insufficiency but is now no longer marketed. It is taken by mouth.

<span class="mw-page-title-main">Noretynodrel</span> Chemical compound

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Trimegestone</span> Chemical compound

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

<span class="mw-page-title-main">17α-Methylprogesterone</span> Chemical compound

17α-Methylprogesterone (17α-MP), or 17α-methylpregn-4-ene-3,20-dione, is a steroidal progestin related to progesterone that was synthesized and characterized in 1949 but was never marketed. Along with ethisterone (1938) and 19-norprogesterone (1951), 17α-MP was one of the earliest derivatives of progesterone to be identified as possessing progestogenic activity. Similarly to progesterone and derivatives like 17α-hydroxyprogesterone and 19-norprogesterone, 17α-MP was found to possess poor oral bioavailability, but showed improved progestogenic activity relative to progesterone when administered via other routes. In addition to its activity as a progestogen, 17α-MP has also been found to possess some antiglucocorticoid activity.

<span class="mw-page-title-main">Gestadienol acetate</span> Chemical compound

Gestadienol acetate an orally active progestin which was described in the literature in 1967 and was never marketed. It has no androgenic or estrogenic effects. The effects of gestadienol acetate on the endometrium and its general pharmacology were studied in a clinical trial in women. It has also been studied in a clinical trial for benign prostatic hyperplasia in men, but was ineffective.

<span class="mw-page-title-main">17α-Allyl-19-nortestosterone</span> Chemical compound

17α-Allyl-19-nortestosterone, also known as 3-ketoallylestrenol or as 17α-allylestr-4-en-17β-ol-3-one, is a progestin which was never marketed. It is a combined derivative of the anabolic–androgenic steroid and progestogen nandrolone (19-nortestosterone) and the antiandrogen allyltestosterone (17α-allyltestosterone). The drug is a major active metabolite of allylestrenol, which is thought to be a prodrug of 17α-allyl-19-nortestosterone.

<span class="mw-page-title-main">18-Methylsegesterone acetate</span> Chemical compound

18-Methylsegesterone acetate is a progestin medication of the 19-norprogesterone group which was never marketed. It was first described in a patent in 1997 and then in a literature paper in 2003. 18-Methyl-SGA is the C18 methyl or C13β ethyl derivative of segesterone acetate, and shows 3 to 10 times the progestogenic potency of SGA in bioassays. This is analogous to the case of the 19-nortestosterone progestin norethisterone and its 18-methyl derivative levonorgestrel, the latter showing substantially increased potency relative to the former similarly. As SGA is already one of the most potent progestins to have been developed, with 100-fold the potency of progesterone and 10-fold the potency of levonorgestrel in bioassays, 18-methyl-SGA is an extremely potent progestogen, among if not the most potent known.

<span class="mw-page-title-main">16-Methylene-17α-hydroxyprogesterone acetate</span> Chemical compound

16-Methylene-17α-hydroxyprogesterone acetate is a progestin of the 17α-hydroxyprogesterone group which was never marketed. Given orally, it shows about 2.5-fold the progestogenic activity of parenteral progesterone in animal bioassays. It is a parent compound of the following clinically used progestins:

<span class="mw-page-title-main">Gestonorone acetate</span> Chemical compound

Gestonorone acetate, or gestronol acetate, also known as norhydroxyprogesterone acetate, is a progestin of the 19-norprogesterone and 17α-hydroxyprogesterone groups which was developed in the early 1960s but was never marketed. It is the C17α acetate ester of gestronol (17α-hydroxy-19-norprogesterone).

References

  1. ↑ Ehrenstein M (1944). "Investigations on Steroids. VIII. Lower Homologs of Hormones of the Pregnane Series: 10-Nor-11-Desoxy-Corticosterone Acetate and 10-Norprogesterone1". The Journal of Organic Chemistry. 09 (5): 435–456. doi:10.1021/jo01187a009. ISSN   0022-3263.
  2. ↑ Allen WM, Ehrenstein M (September 1944). "0-Nor-Progesterone, A Physiologically Active Lower Homolog of Progesterone". Science. 100 (2594): 251–252. Bibcode:1944Sci...100..251A. doi:10.1126/science.100.2594.251. PMID   17738394.
  3. 1 2 3 4 Miramontes L, Rosenkranz G, Djerassi C (1951). "Steroids. XXii. The Synthesis of 19-Norprogesterone". Journal of the American Chemical Society. 73 (7): 3540–3541. doi:10.1021/ja01151a547. ISSN   0002-7863.
  4. 1 2 Djerassi C, Miramontes L, Rosenkranz G (1953). "Steroids. XLVIII. 119-Norprogesterone, a Potent Progestational Hormone". Journal of the American Chemical Society. 75 (18): 4440–4442. doi:10.1021/ja01114a013. ISSN   0002-7863.
  5. ↑ Tullner WW, Hertz R (March 1953). "High progestational activity of 19-norprogesterone". Endocrinology. 52 (3): 359–361. doi:10.1210/endo-52-3-359. PMID   13033848.
  6. 1 2 3 Ravina E (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 187–. ISBN   978-3-527-32669-3.
  7. 1 2 Williams DA, Foye WO, Lemke TL, eds. (January 2002). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 700–. ISBN   978-0-683-30737-5.
  8. 1 2 3 4 5 Paris J, Botella J, Fournau P, Bonnet P, Thevenot R (October 1987). "Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships". The Journal of Pharmacology and Experimental Therapeutics. 243 (1): 288–291. PMID   2822901.
  9. ↑ Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 (Suppl 1): S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID   14670641.
  10. ↑ Sitruk-Ware R (April 2004). "Pharmacological profile of progestins". Maturitas. 47 (4): 277–283. doi:10.1016/j.maturitas.2004.01.001. PMID   15063480.
  11. ↑ Sitruk-Ware R (2004). "New progestogens: a review of their effects in perimenopausal and postmenopausal women". Drugs & Aging. 21 (13): 865–883. doi:10.2165/00002512-200421130-00004. PMID   15493951. S2CID   9543491.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.