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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]
The chemical synthesis has been described:[11][12]Dof:[13] Photoconversion patent:[14]
The more modern Chinese work starts fromdienedione starting material:[15][16] The name of the precursor goes by the trivial name ofEthylene 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).