Development of the selective progesterone receptor modulator CDB-2914 for clinical indications

Blithe, Diana L.; Nieman, Lynnette K.; Blye, Richard P.; Stratton, Pamela; Passaro, Maureen

doi:10.1016/s0039-128x(03)00118-1

Cited by 76 publications

(54 citation statements)

References 16 publications

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“…Other studies evaluating higher doses of CDB-2914 (up to 200 mg) in smaller numbers of women reported no evidence of nausea. 22,23 The value of 29% found in this study may reflect a variable background incidence rather than an increase attributable to the drug itself. This is plausible, because no mechanism has been established by which nausea would be expected to be associated with a progesterone receptor blocker.…”

Section: Discussionmentioning

confidence: 66%

Progesterone Receptor Modulator for Emergency Contraception

Creinin

Schlaff

Archer

et al. 2006

Obstetrics & Gynecology

225

128

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Section: Discussionmentioning

confidence: 66%

Progesterone Receptor Modulator for Emergency Contraception

Creinin

Schlaff

Archer

et al. 2006

Obstetrics & Gynecology

225

128

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“…This compound binds to PGR with high affinity and impairs its generegulatory function (16)(17)(18)(19). Our results indicated that administration of CDB-2914 strongly blocked LH-induced ovulation in mice.…”

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confidence: 60%

A Novel Pathway Involving Progesterone Receptor, Endothelin-2, and Endothelin Receptor B Controls Ovulation in Mice

Palanisamy

Cheon

Kim

et al. 2006

Molecular Endocrinology

114

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The steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (>85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.

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“…All slides were obtained from women currently taking one of the following four PRMs as part of clinical trials: mifepristone (Danco, New York, NY, USA; University of Rochester, Rochester, NY, USA; and University of Edinburgh, Edinburgh, UK), CDB-2914 17 (HRA Pharma, Paris, France); JNJ-17072341 (Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA); or asoprisnil (TAP Pharmaceutical Products Inc., Lake Forest, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

The spectrum of endometrial pathology induced by progesterone receptor modulators

Bergeron²,

et al. 2008

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Progesterone receptor modulators (PRM) are hormonally active drugs effective in the management of endometriosis and uterine leiomyomata. The endometrial effects of progestin blockade by PRMs in premenopausal women are currently being evaluated in several clinical trials, but few pathologists have had access to these materials and published information of the histological changes is scanty. Eighty-four endometrial specimens from women receiving one of four different PRMs were reviewed by a panel of seven experienced gynecologic pathologists to develop consensus observations and interpretive recommendations as part of an NIH-sponsored workshop. Although the pathologists were blinded to agent, dose, and exposure interval, the review was intended to provide an overview of the breadth of possible findings, and a venue to describe unique features. Endometrial histology included inactive and normal-appearing cycling endometrium. Overtly premalignant lesions (atypical hyperplasia or EIN) were not seen. In a subset of cases, asymmetry of stromal and epithelial growth resulted in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects of a type not encountered in contemporary clinical practice. The variety of endometrial appearances suggested that findings might differ by agent and dose over time according to relationships that must be specified for each agent. The constellation of changes seen in those endometria with cystically dilated glands is so novel that new terminology and diagnostic criteria are required for pathologists to recognize them. The panel has designated these changes as PRM-associated endometrial changes (PAEC). Additional follow-up studies will be needed to fully define their natural history and relationship to specific agents and administration regimens.

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Development of the selective progesterone receptor modulator CDB-2914 for clinical indications

Cited by 76 publications

References 16 publications

Progesterone Receptor Modulator for Emergency Contraception

Progesterone Receptor Modulator for Emergency Contraception

A Novel Pathway Involving Progesterone Receptor, Endothelin-2, and Endothelin Receptor B Controls Ovulation in Mice

The spectrum of endometrial pathology induced by progesterone receptor modulators

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