In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone

Attardi, Barbara; Burgenson, Janet; Hild, Sheri Ann; Reel, Jerry R.

doi:10.1016/j.jsbmb.2003.12.004

Cited by 109 publications

(100 citation statements)

References 30 publications

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“…For transient transfection experiments, cells were plated in 6-well dishes in phenol red-free DMEM supplemented with 10% dextran-coated charcoal-stripped (DCC-stripped) fetal bovine serum (FBS, Hyclone Laboratories, Inc., Logan, UT), 10 U/ml penicillin G, and 10 μg/ml streptomycin sulfate. Cells were transfected with 3XERE-LUC, a reporter plasmid containing three copies of an estrogen response element (ERE) upstream of the firefly luciferase (LUC) gene (a gift of Dr. Donald McDonnell, Duke University, Durham, NC) using FuGENE 6 (Roche, Indianapolis, IN) as described previously [3,15]. Data were expressed as relative light units (RLU) normalized for differences in protein content per well.…”

Section: Transcription Assaysmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC 50 's: 5−12 × 10 −9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E 2 ) (EC 50 's: 10 −12 to 10 −11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA,, and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position.

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Section: Transcription Assaysmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…1 Those with potent progesterone antagonist activity, including asoprisnil, 2,3 mifepristone (RU486), 4,5 and CDB-4124 (17a-acetoxy-21-methoxy-11b-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) have great promise as medical therapeutic agents for those gynecologic diseases that are exacerbated by systemic progestins, such as uterine leiomyomata and endometriosis. 6,7 As these are primarily diseases of premenopausal women, patients who are candidates for progesterone receptor modulator medical therapy are likely to be young and have monthly sequential fluctuations of estrogen and progesterone that define their normal menstrual cycle.…”

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confidence: 99%

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

2009

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Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124 (also known as Proellext) for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed endometrial carcinoma or hyperplasia while on therapy. CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other progesterone receptor modulators, including cystic architecture and mixed non-physiologic epithelial changes will prevent misdiagnosis.

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“…VA 2914 is an orally active steroidal SPRM which demonstrates potent PA activity in vivo and in vitro [50] with a reduced anti-glucocorticoid activity compared with mifepristone [51]. This compound shows anti-ovulatory activity and post-coïtal antifertility activity in rats [52].…”

Section: Long-term Contraceptionmentioning

confidence: 99%

Gynaecological uses of a new class of steroids: the selective progesterone receptor modulators

Pintiaux

Chabbert-Buffet

Foidart

2009

Gynecological Endocrinology

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In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone

Cited by 109 publications

References 30 publications

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator

Gynaecological uses of a new class of steroids: the selective progesterone receptor modulators

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