19-Norprogesterone

Chemical compound (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 19-Norprogesterone.svg skin-invert-image 225px Parenteral Progestin; Progestogen; Mineralocorticoid 472-54-8 correct FDA 1A5185976G 228864 199224 10-Norprogesterone; 19-Norpregn-4-ene-3,20-dione; 17β-Acetylestr-4-en-3-one 20 28 2 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 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 NVUUMOOKVFONOM-GPBSYSOESA-N 144 145 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. Ehrenstein M 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 1944 435–456 0022-3263 10.1021/jo01187a009 Allen WM, Ehrenstein M 0-Nor-Progesterone, A Physiologically Active Lower Homolog of Progesterone Science 100 2594 251–252 September 1944 17738394 10.1126/science.100.2594.251 1944Sci...100..251A Miramontes L, Rosenkranz G, Djerassi C Steroids. XXii. The Synthesis of 19-Norprogesterone Journal of the American Chemical Society 73 7 1951 3540–3541 0002-7863 10.1021/ja01151a547 Djerassi C, Miramontes L, Rosenkranz G Steroids. XLVIII. 119-Norprogesterone, a Potent Progestational Hormone Journal of the American Chemical Society 75 18 1953 4440–4442 0002-7863 10.1021/ja01114a013 Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. 19-Norprogesterone was resynthesized in 1951 with an improved method, and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. 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, Tullner WW, Hertz R High progestational activity of 19-norprogesterone Endocrinology 52 3 359–361 March 1953 13033848 10.1210/endo-52-3-359 and at the time of this discovery, 19-norprogesterone was the most potent progestogen known. Ravina E The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA187 11 January 2011 John Wiley & Sons 978-3-527-32669-3 187– Williams DA, Foye WO, Lemke TL Foye's Principles of Medicinal Chemistry https://books.google.com/books?id=qLJ6Bs1Qml4C&pg=PA700 January 2002 Lippincott Williams & Wilkins 978-0-683-30737-5 700– Similarly to progesterone, 19-norprogesterone is a potent progestogen and possesses high affinity for the mineralocorticoid receptor (MR). Paris J, Botella J, Fournau P, Bonnet P, Thevenot R Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships The Journal of Pharmacology and Experimental Therapeutics 243 1 288–291 October 1987 2822901 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. Like progesterone, 19-norprogesterone is very active as a progestogen parenterally but is only minimally active orally. A SAR 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%. 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%). 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. 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. Chemistry Derivatives List of progestogens 19-Norprogesterone is the parent compound of a group of medically used progestins, which includes the following: Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH Classification and pharmacology of progestins Maturitas 46 S7–S16 December 2003 Suppl 1 14670641 10.1016/j.maturitas.2003.09.014 Sitruk-Ware R Pharmacological profile of progestins Maturitas 47 4 277–283 April 2004 15063480 10.1016/j.maturitas.2004.01.001 Sitruk-Ware R New progestogens: a review of their effects in perimenopausal and postmenopausal women Drugs & Aging 21 13 865–883 2004 15493951 10.2165/00002512-200421130-00004 9543491 17α-Hydroxy-19-norprogesterone (gestronol) Gestonorone caproate (17α-hydroxy-19-norprogesterone hexanoate) Nomegestrol acetate (6-methyl-17α-hydroxy-δ6-19-norprogesterone acetate) Norgestomet (11β-methyl-17α-hydroxy-19-norprogesterone acetate) (veterinary) Segesterone acetate (nestorone) (16-methylene-17α-hydroxy-19-norprogesterone acetate) 17α-Methyl-19-norprogesterone (H-3510) Demegestone (17α-methyl-δ9-19-norprogesterone) Promegestone (17α,21-dimethyl-δ9-19-norprogesterone) Trimegestone (21(S)-hydroxy-17α,21-dimethyl-δ9-19-norprogesterone) 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 17α-Methylprogesterone References 2 Category:Diketones Category:Mineralocorticoids Category:Norpregnanes Category:Progestogens Category:Substances discovered in the 1940s