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| Clinical data | |
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| 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 |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.233.493 |
| Chemical and physical data | |
| Formula | C29H39NO3 |
| Molar mass | 449.635 g·mol−1 |
| 3D model (JSmol) | |
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Onapristone (INNTooltip International Nonproprietary Name) (developmental code namesZK-89299,ZK-299) is asynthetic andsteroidalantiprogestogen with additionalantiglucocorticoid activity which was developed bySchering[1] and described in 1984 but was never marketed.[2][3] It is asilent antagonist of theprogesterone receptor (PR), in contrast to the related antiprogestogenmifepristone (which is a weakpartial agonist of thereceptor).[4] Moreover, compared to mifepristone, onapristone has reduced antiglucocorticoid activity, shows littleantiandrogenic activity, and has 10- to 30-fold greaterpotency as an antiprogestogen.[4] The medication was under development for clinical use, for instance in the treatment ofbreast cancer and as anendometrialcontraceptive, but was discontinued duringphase IIIclinical trials in 1995 due to findings thatliver function 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 IIclinical 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]
Reaction of thesteroid derivative (1) and theGrignard reagent 4-(dimethylamino)phenylmagnesium bromide (2) gives (3) byvinylogous addition to theepoxide. Oxidation of thealcohol group in the five-membered ring to a ketone gives compound (4). Irradiation of this material for 16 minutes with a mercury lamp results in the methyl group adjacent to the ketone changing from the beta to the alphaconfiguration, giving (5).Alkynylation with theanion formed from the acetylene derivative (6) usingbutyllithium gives (7).Catalytic hydrogenation to convert the alkyne group to analkyl group, followed by acid treatment to remove theprotecting groups yielded onapristone.[11][12]