CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914

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

doi:10.1016/s0303-7207(01)00743-2

Cited by 112 publications

(91 citation statements)

References 36 publications

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“…The broader clinical utility of RU-486 as a new approach to the treatment of endometriosis, uterine fibroids, and dysfunctional uterine bleeding, for instance, is limited because of antagonism at the glucocorticoid receptor (GR) (Heikinheimo et al, 1987) and effects on corticotropin secretion. Consequently, there has been considerable medicinal chemistry investment focused on identifying alternative chemical equity that has greater selectivity for PR over GR as well as other nuclear hormone receptors (NHRs) (Attardi et al, 2002;Jones et al, 2005;Terefenko et al, 2005;Kern et al, 2007Kern et al, , 2009Kern et al, , 2010Zhang et al, 2007aZhang et al, , 2008Fensome et al, 2008;Dack et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Howe

Mount²,

Bess³

et al. 2011

J Pharmacol Exp Ther

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There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11␤-4-dimethylaminophenyl-17␤-hydroxy-17␣-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.

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Section: Introductionmentioning

confidence: 99%

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Howe

Mount²,

Bess³

et al. 2011

J Pharmacol Exp Ther

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“…CDB-4124, a 21-substituted-19-nor-progestin, is a progesterone receptor modulator originally developed at the National Institutes of Health, 13 currently under license to Repros Therapeutics Inc. (The Woodlands, TX, USA), which is now in phase II clinical trials for the treatment of endometriosis and uterine leiomyomata in premenopausal women. Preliminary data suggest a favorable clinical response of the underlying disease with 3-6 months of CDB-4124 therapy, and studies on the safety of this agent have included biopsies of the endometrium at various intervals to ensure that hyperplasia or carcinoma does not occur at increased frequency.…”

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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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“…As a consequence, RU-486 suppresses the inhibition of corticotropin secretion induced by corticosteroids, limiting its wider usefulness and clinical benefit with escalating doses. Of the many steroidal PR antagonists that have been described, relatively few have been identified that appear to be devoid of antiglucocorticoid activity (Schoonen et al, 1999;Attardi et al, 2002). One of the goals in developing new and selective PR antagonists is the discovery of a simple and efficient screening methodology that identifies these agents and predicts their desired clinical outcome and dose-effect relationship.…”

mentioning

confidence: 99%

The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982)

Giorgio-Miller

Bungay²,

Tutt³

et al. 2008

J Pharmacol Exp Ther

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The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognized as the potential basis for preventing gynecological conditions such as endometriosis and uterine fibroids. In this study, we examine the in vitro and in vivo properties of a nonsteroidal PR antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) in comparison with the nonselective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborization of the rabbit endometrium in a dose-dependent manner at unbound drug exposures that were commensurate with their potencies as PR antagonists in vitro. Translation of this pharmacology to a clinically relevant system was required to bridge the pharmacological gap between nonmenstruating rabbits and humans. Thus, the pharmacokinetic (PK) and pharmacodynamic (PD) data from the rabbit were combined to predict pharmacological effects on the naturally cycling cynomolgus macaque endometrium. PF-02367982 blocked the effect of progesterone on the cynomolgus macaque endometrium to the same degree as RU-486 and at exposures predicted by the rabbit PK-PD model. With such an efficacious and superior selectivity profile to the nonselective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynecological conditions such as endometriosis.The discovery of synthetic progesterone receptor (PR) modulators has underscored the important role that progesterone plays in reproductive physiology, including the menstrual cycle, endometrial growth, breast development and maintenance of pregnancy (Chabbert-Buffet et al., 2005;Spitz, 2006). RU-38486 (RU-486, mifepristone) is the founding member of steroidal PR antagonists and is approved clinically for pregnancy termination and emergency contraception. Studies with RU-486 and other PR antagonists, such as onapristone, ZK-137316 (Zelinski-Wooten et al., 1998), and ZK-230211, have revealed that these agents, as well as directly antagonizing progesterone function, can block ovarian function and also arrest the effect of estrogen on the endometrium in women and nonhuman primates (NHP) (Wolf et al., 1989;Baird et al., 2003;Brenner et al., 2005; ChabbertBuffet et al., 2005;Slayden et al., 2006).The potential usefulness of RU-486 and other PR antagonists in the treatment of pathological conditions such as endometriosis, uterine fibroids, and cancer is supported by a number of preclinical observations and clinical findings (Grow et al., 1996;Kettel et al., 1996;Baird et al., 2003;Fiscella et al., 2006). Although RU-486 has potent antiprogestagenic activity, it is also an equipotent antagonist at the glucocorticoid receptor (GR) (Heikinheimo et al., 1987). As a consequence, RU-486 suppresses the inhibition of corticotropin secretion induced by corticosteroids, limiting its wider usefu...

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CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914

Cited by 112 publications

References 36 publications

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

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

The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982)

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