Onapristone

Onapristone
Clinical data
Other namesZK-89299; ZK-299; AR-18; IVV-1001; 11β-(4-(Dimethylamino)phenyl)-17α-hydroxy-17β-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one
Drug classAntiprogestogen
Identifiers
  • (8S,11R,13R,14S,17S)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.233.493
Chemical and physical data
FormulaC29H39NO3
Molar mass449.635 g·mol−1
3D model (JSmol)
  • C[C@@]12C[C@@H](C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@]2(CCCO)O)C5=CC=C(C=C5)N(C)C
  • InChI=1S/C29H39NO3/c1-28-18-25(19-5-8-21(9-6-19)30(2)3)27-23-12-10-22(32)17-20(23)7-11-24(27)26(28)13-15-29(28,33)14-4-16-31/h5-6,8-9,17,24-26,31,33H,4,7,10-16,18H2,1-3H3/t24-,25+,26-,28+,29+/m0/s1
  • Key:IEXUMDBQLIVNHZ-YOUGDJEHSA-N

Onapristone (INNTooltip International Nonproprietary Name) (developmental code names ZK-89299, ZK-299) is a synthetic and steroidal antiprogestogen with additional antiglucocorticoid activity which was developed by Schering[1] and described in 1984 but was never marketed.[2][3] It is a silent antagonist of the progesterone receptor (PR), in contrast to the related antiprogestogen mifepristone (which is a weak partial agonist of the receptor).[4] Moreover, compared to mifepristone, onapristone has reduced antiglucocorticoid activity, shows little antiandrogenic activity, and has 10- to 30-fold greater potency as an antiprogestogen.[4] The medication was under development for clinical use, for instance in the treatment of breast cancer and as an endometrial contraceptive, but was discontinued during phase III clinical trials in 1995 due to findings that liver function abnormalities developed in a majority patients.[5][6][7]

Onapristone has been found to be effective in the treatment of breast cancer.[8][5][9]

As of 2016, onapristone has re-emerged and is under development for the treatment of prostate cancer, currently in phase II clinical trials.[10] It was also under development for the treatment of endometrial cancer, breast cancer, ovarian cancer, and uterine cancer, but was discontinued for these indications in favor of focusing on prostate cancer.[10]

Chemistry

Synthesis

The chemical synthesis has been described:[11][12] Dof:[13] Photoconversion patent:[14]

The more modern Chinese work starts from dienedione starting material:[15][16] The name of the precursor goes by the trivial name of Ethylene deltenone [5571-36-8].

The conjugate addition reaction between PC10992393 (1) and 4-(n,n-Dimethyl)anilinemagnesium bromide [7353-91-5] (2) gives (3). Oxidation of the 17C alcohol group to a ketone gives [93748-54-0] (4). Irradiation for 16 minutes with a mercury lamp resulted in inversion of the methyl group from the beta to the alpha configuration, PC13371204 (5). Alkynylation with Tetrahydro-2-(2-propynyloxy)-2H-pyran [6089-04-9] (6) in the presence of butyl lithium gave (7). Catalytic hydrogenation then saturated the alkyne group whilst leaving the two olefins unperturbed. Acid removal of the cyclic ketal protecting group then completed the synthesis of onapristone (8).

See also

References

  1. ^ Lange CA, Sartorius CA, Abdel-Hafiz H, Spillman MA, Horwitz KB, Jacobsen BM (2008). "Progesterone receptor action: translating studies in breast cancer models to clinical insights". Advances in Experimental Medicine and Biology. Vol. 630. Springer. pp. 94–111. doi:10.1007/978-0-387-78818-0_7. ISBN 978-0-387-78817-3. PMID 18637487. Onapristone, p. 102, at Google Books
  2. ^ Elks J, Ganellin CR (1990). "O". Dictionary of Drugs. Springer. pp. 892–927. doi:10.1007/978-1-4757-2085-3_15. ISBN 978-1-4757-2087-7. Onapristone, p. 903, at Google Books
  3. ^ Morton IK, Hall JM (1999). "O". Concise Dictionary of Pharmacological Agents. Springer. pp. 206–213. doi:10.1007/978-94-011-4439-1_14. ISBN 978-94-010-5907-7. Onapristone, p. 207, at Google Books
  4. ^ a b Pavlik EJ, Nelson K, Srinivasan S, Depriest PD, Kenady DE (1997). "Antiestrogen Resistance in Human Breast Cancer". Estrogens, Progestins, and Their Antagonists. Hormones in Health and Disease. Birkhäuser. pp. 115–160. doi:10.1007/978-1-4612-4096-9_5. ISBN 978-1-4612-8650-9. Onapristone, p. 134, at Google Books
  5. ^ a b Robertson JF, Willsher PC, Winterbottom L, Blamey RW, Thorpe S (February 1999). "Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer". European Journal of Cancer. 35 (2): 214–218. doi:10.1016/S0959-8049(98)00388-8. PMID 10448262.
  6. ^ Katkam RR, Gopalkrishnan K, Chwalisz K, Schillinger E, Puri CP (September 1995). "Onapristone (ZK 98.299): a potential antiprogestin for endometrial contraception". American Journal of Obstetrics and Gynecology. 173 (3 Pt 1): 779–787. doi:10.1016/0002-9378(95)90341-0. PMID 7573244.
  7. ^ Howell SJ, Howell A (2010). "Endocrine Therapy". Management of Breast Diseases. Springer. pp. 329–352. doi:10.1007/978-3-540-69743-5_18. ISBN 978-3-540-69742-8. Onapristone, p. 338, at Google Books
  8. ^ Klijn JG, Setyono-Han B, Foekens JA (2000). "Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer". Steroids. 65 (10–11): 825–830. doi:10.1016/S0039-128X(00)00195-1. PMID 11108894. S2CID 25524094.
  9. ^ Cottu PH, Bonneterre J, Varga A, Campone M, Leary A, Floquet A, et al. (2018). "Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers". PLOS ONE. 13 (10) e0204973. Bibcode:2018PLoSO..1304973C. doi:10.1371/journal.pone.0204973. PMC 6179222. PMID 30304013.
  10. ^ a b "Onapristone - Context Therapeutics". Adis Insight. Springer Nature Switzerland AG.
  11. ^ EP patent 0129499, Neef G, Sauer G, Wiechert R, Beier S, Elger W, Henderson D, Rohde R, "13-alpha-alkyl gonanes, their preparation and pharmaceutical compositions containing them", issued 1987-12-09, assigned to Schering AG 
  12. ^ Neef G, Beier S, Elger W, Henderson D, Wiechert R (October 1984). "New steroids with antiprogestational and antiglucocorticoid activities". Steroids. 44 (4): 349–372. doi:10.1016/S0039-128X(84)80027-6. PMID 6152725.
  13. ^ Pento, J., Castañer, J. (1995). "Onapristone < Rec INN >". Drugs of the Future. 20 (8): 784. doi:10.1358/dof.1995.020.08.309001. ISSN 0377-8282.
  14. ^ Ulf Tilstam, et al. WO2017053793 (to Context Biopharma Inc).
  15. ^ Synthesis of Progesterone Receptor Antagonist ZK98299[J. Journal of China Pharmaceutical University, 1992, (4): 209-212.]
  16. ^ Synthesis of Progesterone Receptor Antagonist ZK98299 Analogues[J. Journal of China Pharmaceutical University, 1994, (3): 131-134.]
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