Publications (14)36.34 Total impact
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Article: Steroid derivatives as pure antagonists of the androgen receptor.
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ABSTRACT: While the androgens of testicular origin (representing about 50% of total androgens in men over 50 years) can be completely eliminated by surgical or medical castration with GnRH (gonadotropin-releasing hormone) agonists or antagonists, the antiandrogens currently available as blockers of androgen binding to the androgen receptor (AR), namely bicalutamide (BICA), flutamide (FLU) and nilutamide have too weak affinity to completely neutralize the other 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology. Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthesized. Assays of AR binding and activity in carcinoma mouse Shionogi and human LNCaP cells as well as in vivo bioavailability measurements and in vivo prostate weight assays in the rat were used. The chosen lead steroidal compound, namely EM-5854, has a 3.7-fold higher affinity than BICA for the human AR while EM-5855, an important metabolite of EM-5854, has a 94-fold higher affinity for the human AR compared to BICA. EM-5854 and EM-5855 are 14 times more potent than BICA in inhibiting androgen (R1881)-stimulated prostatic specific antigen (PSA) secretion in human prostatic carcinoma LNCaP cells in vitro. MDV3100 has a potency comparable to bicalutamide in these assays. Depending upon the oral formulation, EM-5854 is 5- to 10-times more potent than BICA to inhibit dihydrotestosterone (DHT)-stimulated ventral prostatic weight in vivo in the rat while MDV3100 has lower activity than BICA in this in vivo model. These data are supported by respective 40-fold and 105-fold higher potencies of EM-5854 and EM-5855 compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model. Although the present preclinical results data need evaluation in clinical trials in men, combination of the data obtained in vitro in human LNCaP cells as indicator of potency in the human prostate and the data on metabolism evaluated in vivo on ventral prostate weight in the rat, could suggest the possibility of a 70- to 140-fold higher potency of EM-5854 compared to bicalutamide (Casodex) for the treatment of prostate cancer in men.The Journal of steroid biochemistry and molecular biology 03/2012; 132(1-2):93-104. · 2.66 Impact Factor -
Article: Effect of toremifene and ospemifene, compared to acolbifene, on estrogen-sensitive parameters in rat and human uterine tissues
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ABSTRACT: Background: Although the first generation selective estro-gen receptor modulator (SERM) tamoxifen (TAM) is well known for its uterotrophic activity, this study compares the stimulatory effect of the TAM derivatives toremifene (TORE) and ospemifene (OSPE) on estrogen-sensitive para-meters in rat and human uterine tissues. Material and methods: Ovariectomized female rats were treated daily orally for 10 days with 0.75 mg/rat of TORE, OSPE or acolbifene (ACOL, a pure estrogen antagonist in the uterus and mammary gland), which was used for com-parison. Human endometrial carcinoma Ishikawa cells were incubated for 5 days with increasing doses of compounds, in the absence or presence of 1 nM estradiol (E 2). Results: TORE and OSPE revealed 52% and 56% increases, respectively, in uterine weight, whereas ACOL had no effect. Similar effects were observed on vaginal weight. Endome-trial epithelial height increased from 15.82"0.20 to 48.94" 2.12 and 42.14"1.95 mm with TORE and OSPE, respec-tively, whereas ACOL had no effect. Alkaline phosphatase activity, an estrogen-sensitive parameter in Ishikawa cells, was increased by 144% and 135% with OH-TORE and OH-OSPE, respectively. Owing to their intrinsic estrogenic activ-ity, at maximal concentrations, OH-TORE and OH-OSPE blocked the stimulatory effect of E 2 by only 89% compared to 100% with ACOL. Conclusions: The present in vitro and in vivo data show similar stimulatory effects of 4-hydroxytoremifene (OH-TORE) and OH-OSPE on estrogen-sensitive parameters. ACOL, a third generation SERM, has no effect on any of these parameters. Such data add to the potential uterine safe-ty limitations of triphenylethylene-derived SERMs for long-term use in humans.Horm Mol Biol Clin Invest. 01/2010; 1:139-146. -
Article: Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides
Journal of Labelled Compounds 03/2007; 50(3):197 - 206. -
Article: Inactivation of the pure antiestrogen fulvestrant and other synthetic estrogen molecules by UDP-glucuronosyltransferase 1A enzymes expressed in breast tissue.
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ABSTRACT: Fulvestrant (Faslodex) is administered by intramuscular injection and is converted into ketone, sulfate, sulfone and glucuronide metabolites. Glucuronidation, catalyzed by 18 members of the UDP-glucuronosyltransferase (UGT) enzyme family, plays a major role in the elimination of natural estrogens. The present study was aimed at identifying and characterizing human UGT enzymes involved in the glucuronidation of this antiestrogen as well as other synthetic estrogen derivatives with aliphatic chains on the E2 molecule. In contrast to E2, which is conjugated by UGT1A1, -1A3, -1A8, -1A10, and -2B7, fulvestrant is glucuronidated by UGT1A1, -1A3, -1A4, and -1A8. The four UGT1A-fulvestrant conjugating enzymes glucuronidate this substrate at position 3, whereas only UGT1A8 also produces fulvestrant-17-glucuronide. For E2, only UGT1A3 and UGT2B7 are capable to conjugate at 17-hydroxyposition. These observations indicate that addition of an aliphatic chain to the E2 molecule modifies the specificity of the UGT enzymes toward the C18 molecules. To further investigate the specificity of these enzymes, a series of E2 derivatives with aliphatic or phenyl chains at position 2, 7alpha, and 11beta was also tested for its conjugation with human UGT enzymes. It was observed that, in addition to UGT1A3, UGT1A1 and UGT1A8 also played important roles for the glucuronidation of these compounds. This suggests that the basic structure of E2 is one of the major determinants for the glucuronidation catalyzed by this group of enzymes. Considering the high level of UGT1A3 and -1A4 expression in the gastrointestinal tract and mammary gland, our results suggest that fulvestrant can be inactivated both in intestine and in its target tissue.Molecular Pharmacology 04/2006; 69(3):908-20. · 4.88 Impact Factor -
Article: Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution.
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ABSTRACT: EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively.Journal of Enzyme Inhibition and Medicinal Chemistry 05/2005; 20(2):165-77. · 1.62 Impact Factor -
Article: Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid.
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ABSTRACT: Tetrahydrogestrinone (THG) is a recently identified compound having the greatest impact in the world of sports. In order to obtain a highly accurate and sensitive assessment of the potential anabolic/androgenic activity of THG, we have used microarrays to identify its effect on the expression of practically all the 30,000 genes in the mouse genome and compared it with the effect of dihydrotestosterone (DHT), the most potent natural androgen. Quite remarkably, we found that 671 of the genes modulated by THG in the mouse muscle levator ani are modulated in a similar fashion by DHT, while in the gastrocnemius muscle and prostate, 95 and 939 genes respectively, are modulated in common by the two steroids. On the other hand, THG is more potent than DHT in binding to the androgen receptor, while, under in vivo conditions, THG possesses 20% of the potency of DHT in stimulating prostate, seminal vesicle and levator ani muscle weight in the mouse. The present microarray data provide an extremely precise and unquestionable signature of the androgenic/anabolic activity of THG, an approach which should apply to the analysis of the activity of any anabolic steroid.Journal of Endocrinology 03/2005; 184(2):427-33. · 3.55 Impact Factor -
Article: Synthesis of 14C‐labelled EM‐800 (SCH 57050) and EM‐652·HCl (SCH 57068·HCl, acolbifene), pure selective estrogen receptor modulators
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ABSTRACT: EM-800 (SCH 57050) and EM-652·HCl (SCH 57068·HCl, acolbifene) are orally active pure selective estrogen receptor modulators. The corresponding 14C2-radiolabelled compounds 1 and 2 were synthesized for metabolic studies with uniform labelling of two carbons within the benzene ring of the 2H-1-benzopyran moiety by optical resolution of racemic (±)-[14C2]EM-343 4. This pivotal intermediate amine was prepared in 6 steps with 38% yield from commercially available [U-14C2]resorcinol (3). Resolution by selective crystallization of the diastereomeric mixture of (S)-(+)-camphorsulfonates salts gave the desired (+)-[14C2]EM-652·(+)-CSA 13. Moreover, the racemic amine 4 was recovered from mother liquors by basic treatment, and resolved again. We obtained salt 13, at a 52% yield with 97% diastereomeric excess by repeating the resolution–racemization process. Finally, the corresponding dipivaloate (+)-[14C2]EM-800 1 and hydrochloride salt (+)-[14C2]EM-652·HCl 2 were prepared at respective specific activities of 19.7 and 24.5 µCi/mg with 96.3% radiochemical purity. Copyright © 2004 John Wiley & Sons, Ltd.Journal of Labelled Compounds 08/2004; 47(11):741 - 752. -
Article: Long‐term inhibitory effect of the orally active and pure antiestrogen EM‐800 on the growth of human breast cancer xenografts in nude mice
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ABSTRACT: The antiproliferative effect of the new antiestrogen EM-800 has been studied during 40 weeks of treatment on human breast carcinoma ZR-75–1 xenografts in ovariectomized nude mice supplemented with estrone (0.5 μg, s.c. daily). At the daily 50 μg (approximately 2.5 mg/kg) oral dose, EM-800 caused a complete inhibition of the 680% stimulatory effect of estrone on the growth of the ZR-75–1 human breast cancer xenografts. Complete response, defined as the complete disappearance of the tumors, was observed in 41% of tumors following treatment with the 50 μg dose of the antiestrogen, while a value of 26% was found in ovariectomized animals. The proportion of tumors showing progression at the end of 40 weeks of treatment decreased from 94% in the estrone-supplemented animals to 62%, 61% and 19% in the animals receiving the 5 μg, 20 μg and 50 μg daily doses of the antiestrogen, respectively. None of the tumors that showed a complete or a partial response progressed at later time intervals. The 50 μg daily dose of EM-800 nearly completely (93%) or completely (28% below the value in ovariectomized animals) reversed the stimulatory effect of estrone on uterine and vaginal weight, respectively. The disappearance of 41% of tumors in the group of animals that received the 50 μg daily dose of EM-800 indicates that the antiestrogen induces cell death or apoptosis in ZR-75–1 human breast cancer cells and that its action is cytotoxic and not only cytostatic. Int. J. Cancer 83:424–429, 2000. ©2000 Wiley-Liss, Inc.International Journal of Cancer 01/2000; 85(3):424 - 429. · 5.44 Impact Factor -
Article: Comparative effects of 28‐day treatment with the new anti‐estrogen EM‐800 and tamoxifen on estrogen‐sensitive parameters in intact mice
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ABSTRACT: Following 28 days of oral administration, in intact mice, the novel non-steroidal anti-estrogen EM-800 was at least 30-fold more potent than tamoxifen in inhibiting uterine weight. Moreover, the maximal inhibitory effect achieved with tamoxifen on uterine weight was only 40% that with EM-800. The pure anti-estrogenic activity of EM-800 on the hypothalamo–pituitary-gonadal axis is illustrated by the increase in ovarian weight, while tamoxifen, due to its estrogenic activity, decreased ovarian weight. EM-800 is 10- to 30-fold more potent than tamoxifen in inhibiting uterine and vaginal estrogen receptors. Since 17β-hydroxysteroid dehydrogenase (17β-HSD) is the key enzyme in estradiol formation, the potent inhibitory effect of EM-800 on uterine 17β-HSD could play an additional role by decreasing the availability of estradiol in the uterine tissue, while tamoxifen, on the contrary, stimulates activity of the enzyme. The atrophic changes in both the endometrial and myometrial layers achieved with EM-800 almost reached those observed 28 days after ovariectomy. EM-800 also resulted in a marked decrease in the number of ovarian developing follicles and corpora lutea, while the number of atretic follicles was increased. Tamoxifen treatment, on the other hand, produced an increase in both the number and crowding of the endometrial glands and a mild atrophy of the myometrial layer. Tamoxifen caused atrophic changes of the vaginal epithelium, especially at the highest doses, though the atrophy was much less pronounced than that following EM-800 treatment or ovariectomy. In addition to being at least 30-fold more potent than tamoxifen in inhibiting uterine weight, the novel anti-estrogen causes atrophy of the endometrium, stimulates the hypothalamo–pituitary–gonadal axis and inhibits uterine 17β-HSD activity, while tamoxifen exerts opposite and estrogen-like effects on these parameters. Int. J. Cancer 73:381–391, 1997. © 1997 Wiley-Liss, Inc.International Journal of Cancer 12/1998; 73(3):381 - 391. · 5.44 Impact Factor -
Article: (S)-(+)-4-[7-(2,2-Dimethyl-1-oxopro- poxy)-4-methyl-2-[4-[2-(1-piperidinyl)- ethoxy]phenyl]-2H-1-benzopyran-3-yl]- phenyl 2,2-Dimethylpropanoate (EM-800): A Highly Potent, Specific, and Orally Active Nonsteroidal Antiestrogen
Journal of Medicinal Chemistry 07/1997; 40(14). · 5.25 Impact Factor -
Article: New Highly Stereoselective Synthesis of (Z)-4-Hydroxytamoxifen and (Z)-4-Hydroxytoremifene via McMurry Reaction.
The Journal of Organic Chemistry 06/1996; 61(11):3890-3893. · 4.45 Impact Factor -
Article: New Highly Stereoselective Synthesis of (E)-Droloxifene via Selective Protection of 3,4′-Dihydroxybenzophenone and McMurry Reaction
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ABSTRACT: A new, highly stereoselective synthesis of (E)-droloxifene is reported. Deprotection of 3,4′-dimethoxybenzophenone and selective pivaloylation of the 3′-phenolic position gave 4-hydroxy-3′-(trimethylacetoxy)benzophenone. A McMurry reaction between the preceding benzophenone and propiophenone gave the (E)-olefin as a major product (14:1 E/Z ratio in crude reaction), which was then alkylated with 2-dimethylaminoethyl chloride and deprotected to yield (E)-droloxifene with a >100:1 E/Z ratio (5 steps, 13%). Attempts to use this strategy as a suitable stereoselective method to obtain (Z)-droloxifene were not successful.Tetrahedron. 56(5):703-709. -
Article: Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors
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ABSTRACT: Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7–11 times higher than that of 17β-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20× more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10 000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.The Journal of Steroid Biochemistry and Molecular Biology. -
Article: EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium
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ABSTRACT: Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ERα and ERβ compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ERα and ERβ while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ERα and ERβ and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ERβ, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ERβ activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. When human breast cancer ZR-75-1 xenografts were grown in nude mice, EM-800 led to a complete inhibition of the stimulatory effect of estrogens in ovariectomized mice while tamoxifen was less potent and even stimulated the growth of the tumors in the absence of estrogens, thus illustrating the stimulatory effect of tamoxifen on breast cancer growth. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 had no stimulatory effect on alkaline phosphatase activity, an estrogen-sensitive parameter. Raloxifene, droloxifene, hydroxytoremifene and hydroxytamoxifen, on the other hand, all stimulated to various extent, the activity of this enzyme. The stimulatory effect of all four compounds was blocked by EM-800, thus confirming their estrogenic activity in human endometrial tissue. When administered to ovariectomized animals, EM-800 prevents bone loss, the effect on bone mineral density, trabecular bone volume, and trabecular separation being 5–10 times more potent than raloxifene. EM-800 lowers serum cholesterol and triglyceride levels in the rat as well as in women. In a Phase II study performed in patients with breast cancer showing failure on tamoxifen, 1 patient had a complete response while 5 patients had a partial response and stable disease for at least three months has been observed in an additional 13 patients for a total of 19 positive responses out of 43 evaluable patients (44.2%). No significant secondary effect related to the drug was observed. A phase 3 international clinical trial is currently being performed in tamoxifen failure patients where EM-800 (SCH 57050) is compared to Arimidex. The detailed information obtained at the preclinical level with EM-652 or EM-800 indicates that these orally active compounds are highly potent and pure antiestrogens in the mammary gland and endometrium while they prevent bone loss and lower serum cholesterol and triglyceride levels. Preclinical and clinical data clearly suggest the interest of studying this compound in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer in which settings they should provide additional benefits on bone and lipids.The Journal of Steroid Biochemistry and Molecular Biology · 3.05 Impact Factor
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Institutions
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2004–2005
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University Laval
Québec, Quebec, Canada
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1997–2000
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Centre Hospitalier Universitaire de Québec (CHUQ)
Québec, Quebec, Canada
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