Hydroxyprogesterone acetate

Hydroxyprogesterone acetate
Clinical data
ATC code None
Identifiers
Synonyms Hydroxyprogesterone acetate, acetoxyprogesterone, 17α-acetoxyprogesterone
CAS Number 302-23-8
PubChem (CID) 10156152
ChemSpider 8331660
Chemical and physical data
Formula C23H32O4
Molar mass 372.498 g/mol
3D model (Jmol) Interactive image

Hydroxyprogesterone acetate (OHPA) (INN) (brand name Prodox), or 17α-hydroxyprogesterone acetate, also known as 17α-acetoxyprogesterone or simply acetoxyprogesterone,[1] is an orally active steroidal progestin related to hydroxyprogesterone caproate (OHPC) which was discovered in 1953 and was first marketed by Upjohn in the United States in 1957.[2][3][4][5][6][7][8] It is a derivative of progesterone and the acetate ester of 17α-hydroxyprogesterone, as well as the parent compound of a number of progestins including chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.[4][1]

Pharmacology

OHPA is a progestogen and acts as an agonist of the progesterone receptor (PR), both PRA and PRB isoforms (IC50 = 16.8 nM and 12.6 nM, respectively).[9] It has far (>50-fold) higher affinity for the PR isoforms than 17α-hydroxyprogesterone, a little less than half the affinity of progesterone, and slightly higher affinity than OHPC.[10]

OHPA is of relatively low potency as a progestogen, which may explain its limited relative use.[11] It is 100-fold less potent than medroxyprogesterone acetate, 400-fold less potent than chlormadinone acetate, and 1200-fold less potent than cyproterone acetate in animal assays.[11] In terms of producing full progestogenic changes on the endometrium in women, 75 to 100 mg/day oral OHPA is equivalent to 20 mg/day parenteral progesterone, and OHPA is at least twice as potent as oral ethisterone in such regards.[3] OHPA also is reportedly more potent than OHPC.[9][12]

History

In 1949, it was discovered that 17α-methylprogesterone had twice the progestogenic activity of progesterone when administered parenterally,[13] and this finding led to renewed interest in 17α-substituted derivatives of progesterone as potential progestins.[14] Along with OHPC, OHPA was synthesized by Karl Junkmann of Schering AG in 1953 and was first reported by him in the medical literature in 1954.[15][16][17][18][14] OHPC shows very low oral activity[10] and was introduced for use via intramuscular injection by Squibb in 1956 under the brand name Delalutin.[14] Although a substantial prolongation of action occurs when OHPC is formulated in oil,[10] the same was not observed to a significant extent with OHPA, and this is likely why OHPC was chosen by Schering for development over OHPA.[7]

Subsequently, Upjohn unexpectedly discovered that OHPA, unlike OHPC and progesterone, is orally active and shows marked progestogenic activity with oral administration,[19] a finding that had been missed by the Schering researchers (who were primarily interested in the oil solubility of such esters).[7][14] OHPA was found to possess two to three times the oral activity of 17α-methylprogesterone.[20] Upjohn reported the oral activity of OHPA in the medical literature in 1957 and introduced the drug for medical use as Prodox in 25 mg and 50 mg oral tablet formulations later the same year.[3][14][21] OHPA was indicated for the treatment of a variety of gynecological disorders in women, including secondary amenorrhea, functional uterine bleeding, infertility, habitual abortion, dysmenorrhea, and premenstrual syndrome.[3][21][22] However, it saw relatively little use, which was perhaps due its comparatively low potency relative to a variety of other progestins such as medroxyprogesterone acetate and norethisterone that were introduced around the same time and hence that may have been favored.[11][22]

In 1960, OHPA was introduced as Prodox as an oral progestin for veterinary use for the indication of estrus suppression in dogs.[8][23] However, probably due its high cost and the inconvenience of daily oral administration, the drug was not a market success.[8] It was superseded for this indication by medroxyprogesterone acetate (brand name Promone) in 1963, which could be administered by injection conveniently once every six months, although this preparation was discontinued in 1966 for various reasons and hence was not a market success either.[8]

See also

References

  1. 1 2 Donna Shoupe (7 November 2007). The Handbook of Contraception: A Guide for Practical Management. Springer Science & Business Media. pp. 103–. ISBN 978-1-59745-150-5.
  2. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 664–. ISBN 978-1-4757-2085-3.
  3. 1 2 3 4 DAVIS ME, WIED GL (1957). "17-alpha-HYDROXYPROGESTERONE acetate; an effective progestational substance on oral administration". The Journal of Clinical Endocrinology and Metabolism. 17 (10): 1237–44. doi:10.1210/jcem-17-10-1237. PMID 13475464. It is the purpose of this paper to introduce and describe a new steroid for oral administration, 17-a-hydroxyprogesterone acetate*, and to compare it with the most widely used oral substance with progestational properties, 20,21-anhydro-17-/3-hydroxyprogesterone. * Prodox, Upjohn Co., Kalamazoo, Michigan [...] It was found that 17-a-hydroxyprogesterone acetate has a progestational activity which is at least twice that of anhydrohydroxyprogesterone.
  4. 1 2 Roger Lobo; P.G. Crosignani; Rodolfo Paoletti (31 October 2002). Women’s Health and Menopause: New Strategies - Improved Quality of Life. Springer Science & Business Media. pp. 91–. ISBN 978-1-4020-7149-2.
  5. ↑ James K. Stoller; Franklin A. Michota; Brian F. Mandell (2009). The Cleveland Clinic Foundation Intensive Review of Internal Medicine. Lippincott Williams & Wilkins. pp. 13–. ISBN 978-0-7817-9079-6.
  6. ↑ Enrique Ravina (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 194–. ISBN 978-3-527-32669-3.
  7. 1 2 3 Walter Sneader (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 204–. ISBN 978-0-471-89979-2. In 1954, Karl Junkmann of Schering AG reported that the acetylation of the 17-hydroxyl group of ethisterone provided a derivative suitable for formulating in oil for injection intramuscularly as a depot medication.79 There resulted widespread interest in preparing the acetates (and other esters) of various hydroxy-steroids. One such ester, Upjohn's 17-acetoxyprogesterone, provided to be a promising progestogen even though its hydroxy precursor was inactive. Unfortunately, it turned out that no significant prolongation of action was obtained by formulating it in oil. The Upjohn researchers, however, made the unexpected discovery that their acetoxy derivative was orally active, an observation that had been missed by the Schering group, who were primarily interested in the oil solubility of such esters.
  8. 1 2 3 4 Upjohn Company (1978). Proceedings of the Symposium on Cheque® for Canine Estrus Prevention, Brook Lodge, Augusta, Michigan, March 13-15, 1978. Upjohn Company. p. 16. [...] The first product was 17alpha-acetoxyprogesterone4 (Figure 1) marketed under the trade name of Prodox.® Prodox was introduced in 1960, was designed for oral use and was not a marketing success. The reasons are not clear as to lack of clear success, but one predominant reason was the high cost. For the average size dog, the cost of preventing estrus for a year was approximately $90. In addition, the inconvenience of daily oral administration may have prevented some market acceptance, especially at that cost. In 1963, Upjohn introduced injectable medroxyprogesterone acetate6 (Figure 1) under the trade name of Promone. Injections were to be made every six months, and this procedure was well accepted by both veterinarians and pet owners. However, Promone sales were discontinued in April, 1966 in the United States for basically two reasons. First was a prolonged and unpredictable return to estrus. This appeared to be due to very slow and variable absorption from the injection site. As a result of this variable absorption rate, one would expect a variable return to estrus. Even after [...]
  9. 1 2 Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN (2007). "Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins". American Journal of Obstetrics and Gynecology. 197 (6): 599.e1–7. doi:10.1016/j.ajog.2007.05.024. PMC 2278032Freely accessible. PMID 18060946.
  10. 1 2 3 Shaik, Imam H.; Bastian, Jaime R.; Zhao, Yang; Caritis, Steve N.; Venkataramanan, Raman (2015). "Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats". Xenobiotica. 46 (2): 169–174. doi:10.3109/00498254.2015.1057547. ISSN 0049-8254.
  11. 1 2 3 Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 133–134. ISBN 978-3-642-73790-9.
  12. ↑ Allan C. Barnes (1961). Progesterone. Brook Lodge Press. p. 28. Hydroxyprogesterone cap- roate appears to be even less active than Prodox in some respects. It is about 5 times progesterone as an endometrial stimulator [...]
  13. ↑ Plattner, Pl A., H. Heusser, and P. Th Herzig. "* UBER STEROIDE UND SEXUALHORMONE. 159. DIE SYNTHESE VON 17-METHYL-PROGESTERON." HELVETICA CHIMICA ACTA 32.1 (1949): 270-275.
  14. 1 2 3 4 5 Norman Applezweig (1962). Steroid Drugs. Blakiston Division, McGraw-Hill. pp. 101–102. Junkmann of Schering, AG., however, was able to show that long chain esters of 17a-hydroxyprogesterones such as the 17a-caproate produced powerful long-acting progestational effect. [...] Subsequently, a series of events led to the exploitation of 17a-hydroxyprogesterone derivatives as highly effective and orally active progestogens. Groups at Upjohn, Merck & Co., and Syntex independently found means of readily acetylating the 17-hydroxy group. Later, Upjohn announced it found that 17a-acetoxyprogesterone was orally active in humans and subsequently marketed this compound under the name of Prodox.
  15. ↑ M. Edward Davis. M. Edward Davis Reprints. p. 406. Chemically pure progesterone was the only substance with progestational properties in general use which could be administered parenterally until Junkmann (1) developed in 1953, 17-alpha-hydroxyprogesterone acetate and 17-alpha-hydroxyprogesterone caproate.
  16. ↑ WIED GL, DAVIS ME (1958). "Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates". Ann. N. Y. Acad. Sci. 71 (5): 599–616. PMID 13583817. In the group of new parenteral progestational agents, three substances developed by Karl Junkmann1,2 are the most outstanding and interesting: 17a-hydroxyprogesterone caproate and 17a-hydroxyprogesterone acetate, introduced in 1953, and the most potent of all new parenteral progestational agents, 17-ethynyl-19-nortestosterone enanthate, introduced in 1956.
  17. ↑ ACRH. U.S. Dept. of Energy. 1960. p. 71. [The] minimal activity [of 17(a)-hydroxyprogesterone] is magnified to an unexpected degree by the esterification of this steroid with caproic acid to produce 17(a)-hydroxyprogesterone-17-n-caproate, first reported by Karl Junkmann in 1954.6,7
  18. ↑ Ralph Isadore Dorfman (1966). Methods in Hormone Research. Academic Press. p. 86. Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]
  19. ↑ Veterinary Medicine. 1959. p. 152. Whereas progesterone is relatively inactive when administered orally, ethisterone (anhydrohydroxyprogesterone) and hydroxyprogesterone acetate are highly active.
  20. ↑ Raymond Eller Kirk; Donald Frederick Othmer; Herman Francis Mark (1965). Encyclopedia of chemical technology. Interscience Publishers. p. 78. Subsequent acetylation with acetic anhydride and tosyl acid followed by Oppenauer oxidation afforded 17a-acetoxy- progesterone (95) in good yield (115). Tests showed this compound to possess 2-3 times the oral activity of 17-methylpregn-4-ene-3,20-dione (78) and to be many times more potent than progesterone (116,117).
  21. 1 2 Medical Digest. Medical Digest. Incorporated. 1958. Prodox Tablets ( Upjohn) A new derivative of progesterone for oral administration. Indications: Secondary amenorrhea, functional uterine bleeding, in- fertility, habitual abortion, dysmen-orrhea and premenstrual tension. Supplied: Tablets containing 25 mg. or 50 mg. of hydroxyprogesterone a c e t a te, in bottles of 25 tablets.
  22. 1 2 GREENBLATT RB (1959). "Hormonal control of functional uterine bleeding". Clinical Obstetrics and Gynecology. 2 (1): 232–46. PMID 13639329. [...] ethisterone, 25 mg. (Lutocylol; Pranone) 17-acetoxyprogesterone, 25 mg. (Prodox), 6-methyl-17-acetoxyprogesterone, 5 mg. (Provera), norethindrone, 5 mg. (Norlutin), norethinodrel, 5 mg. (Enovid). [...]
  23. ↑ Pure-bred Dogs, American Kennel Gazette. American Kennel Club. 1961. p. 33. According to Dr. Gordon G. Stocking, director of Upjohn's Veterinary Division, Prodox is a synthetic version of progesterone — one of the hormones that regulates the human female reproductive system. It is 100 per cent effective and has produced no ill-effects on 200 or more dogs on which it has been tested. As a result of its findings, says Dr. Stocking, Upjohn is making the product available through veterinarians.


This article is issued from Wikipedia - version of the 12/2/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.