Onapristone

Onapristone
Clinical data
Other names	ZK-89299; ZK-299; AR-18; IVV-1001; 11β-(4-(Dimethylamino)phenyl)-17α-hydroxy-17β-(3-hydroxypropyl)-13α-estra-4,9-dien-3-one
Drug class	Antiprogestogen
Identifiers
	IUPAC name (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	96346-61-1;
PubChemCID	5311505;
ChemSpider	4470982;
UNII	H6H7G23O3N;
KEGG	D09571;
ChEMBL	ChEMBL1908373;
CompTox Dashboard(EPA)	DTXSID90242210;
ECHA InfoCard	100.233.493
Chemical and physical data
Formula	C29H39NO3
Molar mass	449.635g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 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 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 namesZK-89299,ZK-299) is asyntheticandsteroidal antiprogestogenwith additionalantiglucocorticoidactivity which was developed bySchering^[1]and described in 1984 but was never marketed.^[2]^[3]It is asilent antagonistof theprogesterone receptor(PR), in contrast to the related antiprogestogenmifepristone(which is a weakpartial agonistof thereceptor).^[4]Moreover, compared to mifepristone, onapristone has reduced antiglucocorticoid activity, shows littleantiandrogenicactivity, and has 10- to 30-fold greaterpotencyas an antiprogestogen.^[4]The medication was under development for clinical use, for instance in the treatment ofbreast cancerand as anendometrial contraceptive,but was discontinued duringphase III clinical trialsin 1995 due to findings thatliverfunction abnormalities developed in a majority patients.^[5]^[6]^[7]

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

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

References[edit]

^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, atGoogle Books
^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, atGoogle Books
^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, atGoogle Books
^^a ^bPavlik 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, atGoogle Books
^^a ^bRobertson 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.
^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.
^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, atGoogle Books
^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.
^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.PMC6179222.PMID 30304013.
^^a ^b"Onapristone - Context Therapeutics".Adis Insight.Springer Nature Switzerland AG.

[BersteinSanten2009-1] 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, atGoogle Books

[Elks2014-2] 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, atGoogle Books

[MortonHall1999-3] 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, atGoogle Books

[Pavlik2012-4] 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, atGoogle Books

[pmid10448262-5] 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.

[pmid7573244-6] 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.

[JatoiKaufmann2010-7] 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, atGoogle Books

[pmid11108894-8] 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.

[pmid30304013-9] 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.PMC6179222.PMID 30304013.

[AdisInsight-10] "Onapristone - Context Therapeutics".Adis Insight.Springer Nature Switzerland AG.

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